Cancer-specific molecules and methods of use thereof

ABSTRACT

Disclosed herein are systems and methods for identifying candidate targets that may be used for therapeutic developments. The systems and methods may comprise receiving and analyzing biologically relevant data to identify information or events such as splicing events that may be statistically significant or specific to certain diseases, illnesses or conditions. Also provided are systems and methods for modulating the statistically significant events using compositions or molecules including small molecule compounds, oligonucleotides, proteins or cells.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional PatentApplication No. 62/831,604, filed Apr. 9, 2019, U.S. Provisional PatentApplication No. 62/889,217, filed Aug. 20, 2019, U.S. Provisional PatentApplication No. 62/944,913, filed Dec. 6, 2019, and U.S. ProvisionalPatent Application No. 62/980,900, filed Feb. 24, 2020, each of which ishereby incorporated by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on 16 Dec. 2021, isnamed EVG-002WOC1_SL.txt and is 1,282,000 bytes in size.

BACKGROUND

Cancer and genetic diseases affect more than millions of people in theU.S. Splicing deregulation can be a major hallmark of cancer and geneticdiseases, affecting progression, metastasis, and therapy resistance. RNAsplicing is the process by which introns, the non-protein coding regionsof DNA, are removed from nascent precursor messenger RNA (pre-mRNA), andexons, the protein coding regions of DNA, are joined together to formmature messenger RNA (mRNA). RNA splicing errors may result in splicedRNA that fail to produce functional proteins, thereby causing geneticdiseases including many types of cancers.

SUMMARY

RNA splicing is a form of RNA processing in which a newly made precursormessenger RNA (pre-mRNA) transcript is transformed into a maturemessenger RNA (mRNA). During splicing, introns (intra-genic, non-codingregions) are removed and exons (coding regions) are joined together. RNAsplicing not only provides functional mRNA, but may also be responsiblefor generating additional diversity (i.e., alternative splicing,alternative RNA splicing, or differential splicing). The alternativesplicing may result in the production of different mRNAs from the samegene. The mRNAs that represent isoforms arising from a single gene candiffer by the use of alternative exons or retention of an intron thatdisrupts two exons. This process often leads to different proteinproducts that may have related or drastically different, evenantagonistic, cellular functions. The alternative splicing may compriseone or more of exon skipping or cassette exon, mutually exclusive exons,alternative donor site, alternative acceptor site, intron retention, andany combination or variation thereof.

Multiple studies have shown the oncogenic activity of specific splicingevents and splicing factors, such as SRSF1, SRSF2, ESRP1, and RBFOX1, inhuman and animal models. As such, cancer-associated splicingderegulation may be a novel source of clinically-applicable biomarkersand therapeutic targets.

Provided herein are systems and methods for identifying therapeutictargets (e.g., disease-specific splicing events) in various diseases orillnesses such as cancers. Non-limiting examples of cancers may includeprostate cancer, cancers of barrier tissues (i.e. colorectal cancer,lung cancer) and in other TGFb-rich sites like ovaries,AML/hematological disorders, respiratory system cancer, hepatocellularcarcinoma (liver cancer) which may include both a TGFb-rich environmentand chronic, potentially diet induced inflammation, thoracic cancer,stomach cancer, kidney cancer, pancreatic cancer, skin cancer, orcombinations thereof. Examples of some other diseases may include, butare not limited to, autism (i.e., ST7 (ENV19)), lymphatic disease suchas syndromic lymphedema-genetic disorder and milory disease, eyedegenerative diseases, brain disease- peripheral neuropathy,neurometabolic disease, rare genetic neurological disorders-geneticmotor neuron disease, psychiatric disorders, chronicinflammation/autoimmune disease, including IBD, crohn's disease, andsimilar gastrointestinal disorders, inflammation in pathogenic obesity,including hereditary, childhood, leptin and non-leptin dependentdisease, hypertension and/or other comorbidities associated with westerndiets.

The methods of the present disclosure may also comprise detecting one ormore biomarkers, for example, detecting a presence or an absence ofspecific DNA sequence, mRNA and/or protein isoforms. The presence orabsence of the one or more biomarkers can be used to diagnose diseaseand/or track disease progression.

Also provided herein are methods for modulating therapeutic targets(e.g., disease-specific splicing events) using various types ofmodalities, such as oligonucleotides, small molecules, antibodies, orany combination thereof. In some examples, the modalities may switchpathogenic RNA isoforms to non-pathogenic RNA isoforms. In someexamples, the modalities are oligonucleotides including splicing-switcholigonucleotides (SSO), antisense oligonucleotides (ASO), smallinterfering Ribonucleic Acid (siRNA), conjugated oligonucleotides, or acombination thereof that can knockdown specific isoforms. In some otherexample, the modalities are antibodies or cell-based (e.g., CAR-T) thatmay specifically recognize protein isoform of alternatively spliced RNA,and/or therapeutic compounds including ASO, small molecules or biologicsthat target the isoforms specifically to obtain therapeutic benefit.

Further provided in the present disclosure are methods and systems fortreating diseases or illnesses such as cancers. The systems and methodsmay comprises administering an effective amount to modalities to asubject having the diseases or illnesses. The modalities may beoligonucleotides, small molecules, antibodies, or any combinationthereof, which are designed to achieve disease-specific targeting. Forexample, some of the disease-specific splicing events that have beenidentified can open up grooves for small molecule binding. In that case,small molecules can be designed to target the region that is createdbecause of a splicing change. In another example, splicing changes ofthe membrane bound proteins can display altered surface epitopes thatcan be specifically targeted using antibodies.

An aspect of the present disclosure provides a method of modulatingsplicing in a pre-mRNA in a biological sample comprising: contacting thebiological sample with an antisense compound comprising one or moreoligonucleotides having at least 90% sequence identity tooligonucleotides selected from Tables 2-33.

In some embodiments, the biological sample comprises a cell, a tissue,or a blood sample. In some embodiments, the biological sample is invitro. In some embodiments, the biological sample is a cell. In someembodiments, the method further comprises measuring viability of thecell. In some embodiments, the measuring is over a predetermined timeperiod. In some embodiments, the method further comprises monitoring theviability of the cell over a predetermined time period. In someembodiments, the method further comprises decreasing or increasing aconcentration of the antisense compound based on the viability of thecell. In some embodiments, the method further comprises decreasing orincreasing a concentration of the antisense compound when the viabilityof the cell is below a cut-off value. In some embodiments, the cut-offvalue is about 80%. In some embodiments, the cut-off value is about 90%.In some embodiments, the antisense compound comprises the one or moreoligonucleotides at a concentration of greater than or equal to about300 nM. In some embodiments, the antisense compound comprises the one ormore oligonucleotides at a concentration of less than or equal to about450 nM. In some embodiments, the one or more oligonucleotides comprisedeoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a combinationthereof. In some embodiments, the RNA comprises small interfering RNA(siRNA). In some embodiments, the one or more oligonucleotides comprisessingle-stranded oligonucleotides, double-stranded oligonucleotides, or acombination thereof. In some embodiments, the biological sample is froma subject having or suspected of having a disease or condition. In someembodiments, the disease or condition comprises a genetic disease, a CNSdisease, an inflammatory disease, a neurodegenerative disease, acardiovascular disease, an autoimmune disease, or cancer. In someembodiments, the disease is cancer. In some embodiments, the cancercomprises lung cancer, kidney cancer, or breast cancer. In someembodiments, the breast cancer is triple-negative breast cancer. In someembodiments, the one or more nucleotides comprise oligonucleotidesselected from Tables 2-33. In some embodiments, the one or moreoligonucleotides comprise a modified oligonucleotide. In someembodiments, the modified oligonucleotide comprises at least onemodified internucleoside linkage In some embodiments, the at least onemodified internucleoside linkage is phosphorothioate linkage In someembodiments, the modified oligonucleotide comprises one or more modifiednucleotides. In some embodiments, the modified oligonucleotide comprisesone or more modified nucleosides. In some embodiments, a modifiednucleoside of the one or more modified nucleosides comprises a modifiedsugar moiety. In some embodiments, the modified sugar moiety is a2′-substituted sugar moiety. In some embodiments, the 2′-substitutedsugar moiety comprises a modification selected from the group consistingof 2′-O-methoxyethyl, 2′-fluoro, 2′-dimethylaminooxyethoxy,2′-dimethylaminoethoxyethoxy, 2′-guanidinium, 2′-O-guanidinium ethyl,2′-carbamate, 2′aminooxy, 2′-acetamido, and locked nucleic acid. In someembodiments, the modified oligonucleotide comprises a plurality ofmodified nucleosides each comprising a modified sugar moiety. In someembodiments, at least a subset of the plurality of modified nucleosidesare different from one another. In some embodiments, the modulatingcomprises inducing or enhancing exon skipping. In some embodiments, themodulating comprises inducing or enhancing exon inclusion. In someembodiments, the modulating comprises promoting a splicing switch. Insome embodiments, the modulating comprises down-regulation orup-regulation of splicing. In some embodiments, the antisense compoundspecifically binds to a segment of a pre-mRNA encoded by a genecomprising NEDD4L, MAP3K7, NFYA, ESYT2, MARK2, ST7, ARVCF, SYTL2,R3HDM1,COL4A3BP, TANGO2, SEPT9, ROBO1,FAM122B, CD47, LSR, PBX1,EPB41,ADAM15, EPB41L1, ABI1, FLNB, CTNND1, GPR160, ITGB3BP, INCENP, DENND1B,or CA12.

Another aspect of the present disclosure provides a pharmaceuticalcomposition comprising (i) an antisense compound comprising one or moreoligonucleotides having at least 90% sequence identity tooligonucleotides selected from Tables 2-33, and (ii) a pharmaceuticallyacceptable diluent or carrier.

In some embodiments, the antisense compound comprises the one or moreoligonucleotides at a concentration of greater than or equal to about300 nM. In some embodiments, the antisense compound comprises the one ormore oligonucleotides at a concentration of less than or equal to about450 nM. In some embodiments, the one or more oligonucleotides comprisedeoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a combinationthereof. In some embodiments, the RNA comprises small interfering RNA(siRNA). In some embodiments, the one or more oligonucleotides comprisessingle-stranded oligonucleotides, double-stranded oligonucleotides, or acombination thereof. In some embodiments, the pharmaceutical compositionis used for treating or alleviating a disease or condition. In someembodiments, the disease comprises a genetic disease, a CNS disease, aninflammatory disease, a neurodegenerative disease, a cardiovasculardisease, an autoimmune disease, or cancer. In some embodiments, thedisease or condition is cancer. In some embodiments, the cancercomprises lung cancer, kidney cancer, or breast cancer. In someembodiments, the breast cancer is triple-negative breast cancer. In someembodiments, the one or more nucleotides comprise oligonucleotidesselected from Tables 2-33. In some embodiments, the one or moreoligonucleotides comprise a modified oligonucleotide. In someembodiments, the modified oligonucleotide comprises at least onemodified internucleoside linkage In some embodiments, the at least onemodified internucleoside linkage is phosphorothioate linkage In someembodiments, the modified oligonucleotide comprises one or more modifiednucleotides. In some embodiments, the modified oligonucleotide comprisesone or more modified nucleosides. In some embodiments, a modifiednucleoside of the one or more modified nucleosides comprises a modifiedsugar moiety. In some embodiments, the modified sugar moiety is a2′-substituted sugar moiety. In some embodiments, the 2′-substitutedsugar moiety comprises a modification selected from the group consistingof 2′-O-methoxyethyl, 2′-fluoro, 2′-dimethylaminooxyethoxy,2′-dimethylaminoethoxyethoxy, 2′-guanidinium, 2′-O-guanidinium ethyl,2′-carbamate, 2′aminooxy, 2′-acetamido, and locked nucleic acid. In someembodiments, the modified oligonucleotide comprises a plurality ofmodified nucleosides each comprising a modified sugar moiety. In someembodiments, at least a subset of the plurality of modified nucleosidesare different from one another. In some embodiments, the pharmaceuticalcomposition is used for modulating splicing of a pre-mRNA encoded by agene comprising NEDD4L, MAP3K7, NFYA, ESYT2, MARK2, ST7, ARVCF, SYTL2,R3HDM1, COL4A3BP, TANGO2, SEPT9, ROBO1, FAM122B, CD47, LSR, PBX1, EPB41,ADAM15, EPB41L1, ABI1, FLNB, CTNND1, GPR160, ITGB3BP, INCENP, DENND1B,or CA12. In some embodiments, the modulating comprises inducing orenhancing exon skipping. In some embodiments, the modulating comprisesinducing or enhancing exon inclusion. In some embodiments, themodulating comprises promoting a splicing switch. In some embodiments,the modulating comprises down-regulation or up-regulation of splicing.

Another aspect of the present disclosure provides an antisense compoundfor use in preparation of a medicament for the treatment of a disease ora condition, the antisense compound comprising one or moreoligonucleotides having at least 90% sequence identity tooligonucleotides selected from Tables 2-33.

In some embodiments, the antisense compounds comprise the one or moreoligonucleotides at a concentration of greater than or equal to about300 nM. In some embodiments, the antisense compound comprises the one ormore oligonucleotides at a concentration of the concentration is lessthan or equal to about 450 nM. In some embodiments, the one or moreoligonucleotides comprise deoxyribonucleic acid (DNA), ribonucleic acid(RNA), or a combination thereof. In some embodiments, the RNA comprisessmall interfering RNA (siRNA). In some embodiments, the one or moreoligonucleotides comprises single-stranded oligonucleotides,double-stranded oligonucleotides, or a combination thereof. In someembodiments, the disease or condition comprises a genetic disease, a CNSdisease, an inflammatory disease, a neurodegenerative disease, acardiovascular disease, an autoimmune disease, or cancer. In someembodiments, the disease is cancer. In some embodiments, the cancercomprises lung cancer, kidney cancer, or breast cancer. In someembodiments, the breast cancer is triple-negative breast cancer. In someembodiments, the one or more nucleotides comprise oligonucleotidesselected from Tables 2-33. In some embodiments, the one or moreoligonucleotides comprise a modified oligonucleotide. In someembodiments, the modified oligonucleotide comprises at least onemodified internucleoside linkage. In some embodiments, the at least onemodified internucleoside linkage is phosphorothioate linkage. In someembodiments, the modified oligonucleotide comprises one or more modifiednucleotides. In some embodiments, the modified oligonucleotide comprisesone or more modified nucleosides. In some embodiments, a modifiednucleoside of the one or more modified nucleosides comprises a modifiedsugar moiety. In some embodiments, the modified sugar moiety is a2′-substituted sugar moiety. In some embodiments, the 2′-substitutedsugar moiety comprises a modification selected from the group consistingof 2′-O-methoxyethyl, 2′-fluoro, 2′-dimethylaminooxyethoxy,2′-dimethylaminoethoxyethoxy, 2′-guanidinium, 2′-O-guanidinium ethyl,2′-carbamate, 2′aminooxy, 2′-acetamido and locked nucleic acid. In someembodiments, the modified oligonucleotide comprises a plurality ofmodified nucleosides each comprising a modified sugar moiety. In someembodiments, at least a subset of the plurality of modified nucleosidesare different from one another. In some embodiments, the treatmentcomprising modulating splicing of a pre-mRNA encoded by a genecomprising NEDD4L, MAP3K7, NFYA, ESYT2, MARK2, ST7, ARVCF, SYTL2,R3HDM1, COL4A3BP, TANGO2, SEPT9, ROBO1, FAM122B, CD47, LSR, PBX1, EPB41,ADAM15,EPB41L1, ABI1, FLNB,CTNND1, GPR160, ITGB3BP, INCENP,DENND1B, orCA12. In some embodiments, the modulating comprises inducing orenhancing exon skipping. In some embodiments, the modulating comprisesinducing or enhancing exon inclusion. In some embodiments, themodulating comprises promoting a splicing switch. In some embodiments,the modulating comprises down-regulation or up-regulation of splicing.

Another aspect of the present disclosure provides a method of modulatingsplicing in a pre-mRNA in a biological sample comprising: contacting thebiological sample with a composition which specifically binds to asegment of the pre-mRNA which is encoded by a gene selected from thegroup consisting of NEDD4L, MAP3K7, NFYA, ESYT2, MARK2, ST7, ARVCF,SYTL2, R3HDM1,COL4A3BP, TANGO2, SEPT9, ROBO1, FAM122B, CD47, LSR,PBX1,EPB41, ADAM15,EPB41L1, ABI1, FLNB,CTNND1, GPR160, ITGB3BP, INCENP,DENND1B, and CA12.

In some embodiments, the segment of the pre-mRNA is 9-150 nucleotides inlength. In some embodiments, the composition comprises oligonucleotides.In some embodiments, the oligonucleotides are sufficiently complementaryto the segment of the pre-mRNA. In some embodiments, theoligonucleotides have at least 80% sequence identity to the segment ofthe pre-mRNA. In some embodiments, the oligonucleotides have at least90% sequence identity to the segment of the pre-mRNA. In someembodiments, the oligonucleotides comprise 10-50 nucleotides. In someembodiments, the oligonucleotides comprise 15-30 nucleotides. In someembodiments, the composition comprises small molecules, nucleic acidmolecules, engineered cells, proteins, or a combination or modificationthereof. In some embodiments, the composition comprises a chimericmolecule. In some embodiments, the chimeric molecule comprises a nucleicacid molecule and a protein. In some embodiments, the nucleic acidmolecule comprises DNA, RNA, PNA, or a combination or hybrid thereof. Insome embodiments, the composition induces or enhances exon skipping inthe pre-mRNA. In some embodiments, the composition induces or enhancesexon inclusion in the pre-mRNA. In some embodiments, the compositionpromotes a splicing switch in the pre-mRNA. In some embodiments, thecomposition down-regulates or up-regulates of splicing in the pre-mRNA.In some embodiments, the composition prevents splicing in the pre-mRNA.

Another aspect of the present disclosure provides a method for treatinga disease or condition in a subject in need thereof, comprising:administering an effective amount of a composition to the subject, whichcomposition specifically binds to a segment of a pre-mRNA which isencoded by a gene selected from the group consisting of NEDD4L, MAP3K7,NFYA, ESYT2, MARK2, ST7, ARVCF, SYTL2, R3HDM1, COL4A3BP, TANGO2, SEPT9,ROBO1, FAM122B, CD47, LSR, PBX1, EPB41, ADAM15, EPB41L1, ABI1, FLNB,CTNND1, GPR160, ITGB3BP, INCENP, DENND1B, and CA12, thereby modulatingsplicing in the pre-mRNA.

In some embodiments, the segment of the pre-mRNA is 9-150 nucleotides inlength. In some embodiments, the composition comprises oligonucleotides.In some embodiments, the oligonucleotides are sufficiently complementaryto the segment of the pre-mRNA. In some embodiments, theoligonucleotides have at least 80% sequence identity to the segment ofthe pre-mRNA. In some embodiments, the oligonucleotides have at least90% sequence identity to the segment of the pre-mRNA. In someembodiments, the oligonucleotides comprise 10-50 nucleotides. In someembodiments, the oligonucleotides comprise 15-30 nucleotides. In someembodiments, the composition comprises small molecules, nucleic acidmolecules, engineered cells, proteins, or a combination or modificationthereof. In some embodiments, the composition comprises a chimericmolecule. In some embodiments, the chimeric molecule comprises a nucleicacid molecule and a protein. In some embodiments, the nucleic acidmolecule comprises DNA, RNA, PNA, or a combination or hybrid thereof. Insome embodiments, the composition induces or enhances exon skipping inthe pre-mRNA. In some embodiments, the composition induces or enhancesexon inclusion in the pre-mRNA. In some embodiments, the compositionpromotes a splicing switch in the pre-mRNA. In some embodiments, thecomposition down-regulates or up-regulates of splicing in the pre-mRNA.In some embodiments, the composition prevents splicing in the pre-mRNA.In some embodiments, the effective amount comprises at least 300 nM ofthe composition. In some embodiments, the effective amount comprises atmost 500 nM of the composition. In some embodiments, the disease orcondition comprises a genetic disease, a CNS disease, an inflammatorydisease, a neurodegenerative disease, a cardiovascular disease, anautoimmune disease, or cancer. In some embodiments, the disease orcondition is cancer. In some embodiments, the cancer comprises lungcancer, kidney cancer, or breast cancer. In some embodiments, the breastcancer is triple negative breast cancer.

Another aspect of the present disclosure provides a method forscreening, diagnosis or prognosis of a disease or condition in asubject, comprising: (a) analyzing a biological sample from the subjectto detect a level of expression of a protein isoform, which proteinisoform is encoded by a gene selected from the group consisting ofNEDD4L, MAP3K7, NFYA, ESYT2, MARK2, ST7, ARVCF, SYTL2, R3HDM1, COL4A3BP,TANGO2, SEPT9, ROBO1, FAM122B, CD47, LSR, PBX1, EPB41, ADAM15, EPB41L1,ABI1, FLNB, CTNND1, GPR160, ITGB3BP, INCENP, DENND1B, and CA12; and (b)determining a difference of the level of expression of the proteinisoform in the biological sample relative to a level of expression ofthe protein isoform in a biological sample of a control, wherein thedifference is indicative or predicative of the disease or condition.

In some embodiments, the biological sample is a cell, a tissue, or ablood sample. In some embodiments, (a) comprises quantitativelydetecting an amount of the protein isoform in the biological sample. Insome embodiments, the difference comprises an increase or a decrease ofthe level of expression of the protein isoform in the biological samplerelative to the level of expression of the protein isoform in thebiological sample of the control. In some embodiments, the increase ofthe level of expression of the protein isoform in the biological samplerelative to the level of expression of the protein isoform in thebiological sample of the control is indicative or predicative of thedisease or condition. In some embodiments, the decrease of the level ofexpression of the protein isoform in the biological sample relative tothe level of expression of the protein isoform in the biological sampleof the control is indicative or predicative of the disease or condition.In some embodiments, the protein isoform comprises alternatively splicedprotein isoforms. In some embodiments, the alternatively spliced proteinisoforms are formed by alternative splicing of the gene. In someembodiments, the alternative splicing comprises exon skipping, exoninclusion, intron retention, competing 5′ splice sites, competing 3′splice sites, multiple promoters, multiple poly(A) sites or acombination thereof. In some embodiments, the method further comprisesdetecting a level of expression of the gene in the biological sample. Insome embodiments, the method further comprises detecting a presence oran absence of a difference of the level of expression of the gene in thebiological sample of the subject relative to a level of expression ofthe gene in the biological sample in the control. In some embodiments,the presence or the absence of the difference of the level of expressionof the gene is further indicative or predicative of the disease orcondition. In some embodiments, the presence of the difference comprisesan increase or a decrease of the level of expression of the gene in thebiological sample of the subject relative to the level of expression ofthe gene in the biological sample in the control. In some embodiments,the method further comprises monitoring a progression of the disease orcondition in the subject. In some embodiments, the monitoring comprisesrepeating (a) multiple times over a predetermined time period. In someembodiments, the method further comprises providing a treatment to thesubject upon diagnosis of the disease or condition in the subject. Insome embodiments, the treatment comprises administering to the subjectan effective amount of a composition which modulates the level of theprotein isoform expression. In some embodiments, the treatment comprisesadministering to the subject an effective amount of a composition whichmodulates splicing of the gene encoding the protein isoform. In someembodiments, the disease or condition comprises a genetic disease, a CNSdisease, an inflammatory disease, a neurodegenerative disease, acardiovascular disease, an autoimmune disease, or cancer. In someembodiments, the disease or condition is cancer. In some embodiments,the cancer comprises lung cancer, kidney cancer, or breast cancer. Insome embodiments, the breast cancer is triple negative breast cancer.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings (also “Figure” and “FIG.” herein), of which:

This patent or application file contains at least one drawing executedin color. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 shows an exemplary oncoprint summary of recurring genomicaberration and transcriptional changes for splicing associated RNAbinding proteins in triple-negative breast cancer (TNBC) patientsamples.

FIG. 2 schematically illustrates an example of luminal versus TNBCRNA-seq data analysis and target selection.

FIG. 3 shows an examplary diagram of splicing changes in the CancerGenome Atlas (TCGA) and cell lines showing independent and overlappingevents.

FIG. 4 shows examplary reverse transcription polymerase chain reaction(RT-PCR) images showing differential splicing of selected candidates inluminal versus TNBC cell lines.

FIG. 5 shows exemplary Western blot of protein lysates from luminal andbasal cell lines showing the isoform expression at the protein level fordifferent genes.

FIG. 6 shows a survival analysis of breast cancer patients expressingNEDD4L inclusion versus skipped isoforms showing poor overall survivalfor patents with skipped isoform.

FIG. 7 shows comparison of splicing differences and total geneexpression differences across multiple breast cancer subtypes.

FIG. 8 illustrate SpliceLearn scores and corresponding eCLIP peaksaround the NEDD4L exon trio. The scores can be used for designing oligosequences and the bottom panel shows the splice switching experimentalresults in which the high scoring ASOs (GTGGGTTTCAGGGATTCTGA (SEQ ID NO:1), CCCTGATTCAGACAGCAGGG (SEQ ID NO:2) significantly switched to theinclusion isoform in MDA-MB-231 cells.

FIG. 9 shows an exemplary experimental validation and quantitation ofswitching off NEDD4L in MCF7 and MDA-Mb-231 cells treated with 400 nMspecific oligos and controls treated with either lipofectamine or PBS.Radioactive RT-PCR is shown above and quantitation of the results isshown below.

FIG. 10A shows an exemplary dose response curve for an SSO(GTGGGTTTCAGGGATTCTGA (SEQ ID NO: 1)) targeting NEDD4L which promotesinclusion. The SSO treatment causes dose dependent viability loss inMDA-Mb-231 cells compared to MCF7 cells. The optimal LC50 value is about370 nM.

FIG. 10B shows an exemplary dose response curve for an SSO(CCCTGATTCAGACAGCAGGG (SEQ ID NO: 2)) targeting NEDD4L which promotesinclusion. SSO treatment causes dose dependent viability loss inMDA-Mb-231 cells compared to MCF7 cells. The optimal LC50 value is about420 nM.

FIG. 11 shows exemplary PCR validations for a candidate gene.

FIG. 12 shows exemplary PCR validations for a candidate gene.

FIG. 13 shows exemplary PCR validations for a candidate gene.

FIG. 14 shows exemplary PCR validations for a candidate gene.

FIG. 15 shows an exemplary survival analysis of breast cancer patientsexpressing long and short isoforms for a candidate gene.

FIG. 16 shows an exemplary survival analysis of breast cancer patientsexpressing long and short isoforms for a candidate gene.

FIG. 17 shows an example selection criteria table.

FIG. 18 shows how the selection criteria is used to identify more targetgenes than use of splicing alone.

DETAILED DESCRIPTION

While various embodiments of the invention have been shown and describedherein, it will be obvious to those skilled in the art that suchembodiments are provided by way of example only. Numerous variations,changes, and substitutions may occur to those skilled in the art withoutdeparting from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein may beemployed.

Whenever the term “at least,” “greater than,” or “greater than or equalto” precedes the first numerical value in a series of two or morenumerical values, the term “at least,” “greater than” or “greater thanor equal to” applies to each of the numerical values in that series ofnumerical values. For example, greater than or equal to 1, 2, or 3 isequivalent to greater than or equal to 1, greater than or equal to 2, orgreater than or equal to 3.

Whenever the term “no more than,” “less than,” or “less than or equalto” precedes the first numerical value in a series of two or morenumerical values, the term “no more than,” “less than,” or “less than orequal to” applies to each of the numerical values in that series ofnumerical values. For example, less than or equal to 3, 2, or 1 isequivalent to less than or equal to 3, less than or equal to 2, or lessthan or equal to 1.

Identification of Candidate Targets for Therapeutic Development

In some aspects of the present disclosure, methods and systems fordetecting or identifying candidate drug targets are provided. Thecandidate drug targets may be associated with specific diseases,illnesses or conditions. The diseases, illnesses or conditions maycomprise cancer. Non-limiting examples of diseases, illnesses orconditions may include but not limited to ductal carcinoma in ducttissue in a mammary gland, medullary carcinomas, colloid carcinomas,tubular carcinomas, breast cancer or subtypes thereof; ovarian cancer,including epithelial ovarian tumors such as adenocarcinoma in the ovaryand an adenocarcinoma that has migrated from the ovary into theabdominal cavity, uterine cancer, cervical cancer such as adenocarcinomain the cervix epithelial including squamous cell carcinoma andadenocarcinomas; prostate cancer, such as a prostate cancer selectedfrom the following: an adenocarcinoma or an adenocarcinoma that hasmigrated to the bone; pancreatic cancer such as epithelioid carcinoma inthe pancreatic duct tissue and an adenocarcinoma in a pancreatic duct;bladder cancer such as a transitional cell carcinoma in urinary bladder,urothelial carcinomas (transitional cell carcinomas), tumors in theurothelial cells that line the bladder, squamous cell carcinomas,adenocarcinomas, and small cell cancers; leukemia such as acute myeloidleukemia (AML), acute lymphocytic leukemia, chronic lymphocyticleukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia(CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bonecancer; lung cancer such as non-small cell lung cancer (NSCLC), which isdivided into squamous cell carcinomas, adenocarcinomas, and large cellundifferentiated carcinomas, and small cell lung cancer; skin cancersuch as basal cell carcinoma, melanoma, squamous cell carcinoma andactinic keratosis, which is a skin condition that sometimes developsinto squamous cell carcinoma; eye retinoblastoma; cutaneous orintraocular (eye) melanoma; primary liver cancer (cancer that begins inthe liver); kidney cancer; thyroid cancer such as papillary, follicular,medullary and anaplastic; AIDS-related lymphoma such as diffuse largeB-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleavedcell lymphoma; Kaposi's Sarcoma; viral-induced cancers includinghepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellularcarcinoma; human lymphotropic virus-type 1 (HTLV-1) and adult T-cellleukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer;central nervous system cancers (CNS) such as primary brain tumor, whichincludes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastomamultiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma,Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancerssuch as acoustic neuromas and malignant peripheral nerve sheath tumor(MPNST) including neurofibromas and schwannomas, malignant fibrouscytoma, malignant fibrous histiocytoma, malignant meningioma, malignantmesothelioma, and malignant mixed Mtillerian tumor; oral cavity andoropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer,nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such aslymphomas, gastric stromal tumors, and carcinoid tumors; testicularcancer such as germ cell tumors (GCTs), which include seminomas andnonseminomas, and gonadal stromal tumors, which include Leydig celltumors and Sertoli cell tumors; thymus cancer such as to thymomas,thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids orcarcinoid tumors; rectal cancer; and colon cancer. In some embodiments,the pharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e. g., benign prostatichypertrophy (BPH)).

The candidate drug targets may comprise one or more genes that aredifferentially express, exons (e.g., exon duos or exon trios) that aredifferentially spliced, or a combination thereof. The methods andsystems can be exon-centric and highly sensitive in detectinglow-abundance aberrant mRNA isoforms.

Additionally, artificial intelligence (AI) may be utilized by themethods and systems as provided herein. The AI may comprise the use ofmachine learning algorithms, non-limiting examples of which may comprisesupervised (or predictive) learning, semi-supervised learning, activelearning, unsupervised machine learning, or reinforcement learning,support vector machines (SVM), linear, logistics, tress, random forest,xgboost, neural networks, deep neural networks, boosting techniques,bootstrapping techniques, ensemble techniques, or combinations thereof.

As provided herein, the systems or methods may comprise receiving datafrom a database. The database may be a public database (e.g., TCGA,GTEX, dbGAP), a private database, or a combination thereof. The databasemay comprise public data, proprietary data, or a combination thereof.The database may comprise clinical or biological data. The database maycomprise RNA-seq data. The database may comprise data obtained from avariety of samples, e.g., greater than or equal to about 100, 200, 300,400, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000,7,000, 8,000, 9,000, 10,000, 15,000, 20,000, 25,000, 30,000, 40,000,50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 125,000, 150,000,175,000, 200,000 samples, or more. At least a subset of the samples maybe obtained from different subjects have the same or different diseases,illnesses or conditions.

The database may comprise data extracted or derived from samples fromcell lines from certain diseases, illnesses or conditions, and/or fromsubjects having certain different diseases, illnesses or conditions. Insome cases, the diseases, illnesses or conditions comprise breast canceror subtypes thereof, for example, liminal A, luminal B, Her2+, TNBC.Non-limiting examples of cell lines may comprise BT483, CAMA1, EFM19,HCC1428, HCC712, IBEP2, KPL1, LY2, MCF7, MDAMB 134, MDAMB134V1, MDAMB157, MDAMB 175, MDAMB175VII, MDAMB231, MDAMB330, MDAMB361, MDAMB415,MDAMB435, MDAMB436, MDAMB453, MDAMB468, T47D, ZR751, ZR75B, BSMZ, BT474,EFM192A,IBEP1, IBEP3, UACC812, ZR7527, ZR7530, 21MT1, 21MT2, 21NT, 21PT,AU565, HCC1008, HCC1569, HCC1954, HCC202, HCC2218, HH315, HH375, KPL-4,OCUB-F, SKBR3, SKBRS, SUM19OPT, SUM225CWN, UACC893, BT20, CAL148,DU4475, EMG3, HCC38, HCC1143,HCC1187, HCC1395, HCC1599, HCC1739,HCC1806, HCC1937, HCC2157, HCC3153, HCC70, HMT3522, KPL-3C, MA11,MFM223,SUM185PE, SUM229PE, BT549, CAL120, CAL851, HDQ-P1, Hs578T, SKBR7,SUM102PT, SUM1315M02, SUM149PT, SUM159PT, or any combination thereof.

The data may be subject to one or more analysis or processing steps. Thedata may be analyzed and/or quantified to identify information orevent(s) such as a splicing event. The information or event(s)identified may be statistically significant or specific to one or morediseases, illnesses or conditions. The data analysis or processing maycomprise mapping the data to genomes, transcriptomes, or a combinationthereof. The data may be processed to remove any information that maynot be related to genomes, transcriptomes, or a combination thereof. Thedata may be processed or analyzed based on one or more predeterminedparameters or criteria including, such as types or subtypes of diseases,illnesses, or conditions.

In cases where a database comprises data associated with different typesor subtypes of diseases, illnesses, or conditions, data related to eachtype or subtype may be analyzed or processed individually to identifyinformation or an event(s) that may be statistically significant orspecific to each type or subtype. The identified information or event(s)may be grouped together and compared to one or more controls todetermine one or more candidate targets. Alternatively, the informationor event(s) identified for each subtype or type may be compared with oneanother to generate a list of candidate targets. In some cases, thecandidate targets comprise information or an event(s) that is identifiedor shared by at least two different types or subtypes.

The list of candidate targets may comprise any number of candidatetargets, for example, greater than or equal to about 5, 10, 20, 30, 40,50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280,300, 350, 400, 450, 500, or more. In some cases, the list may comprise anumber of candidate targets falling between any of the two valuesdescribed above, for example, about 275.

At least a portion (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, or more) of the candidate targets generated may besubjected to further data analysis or processing. The candidate targetsmay be arranged in certain order based upon one or more parameters orcriteria. The candidate targets may be selected based upon one or moreparameters or criteria, thereby generating a refined list of candidatetargets. Non-limiting examples of the parameters which may be used toarrange the candidate targets comprise a splicing index, a diseaseindex, a splice-switching oligonucleotides (SSO) druggability index, orany combination thereof.

The splicing index may be determined based at least in part on factorsincluding e.g., splicing change in a sample (or data) analyzed ascompared to a control, consistency and/or reproducibility of a giveninformation or event(s) (e.g., in patient dataset(s)), recurrence of agiven information or event(s) in multiple disease datasets, an absenceof a given information or event in a normal or control dataset(s). Eachfactor may be given the same or a different weight in the determinationand based on the determination, a score may be generated.

The disease index may be determined based at least in part on factorsincluding e.g., an impact of a given information or event(s) such as asplice change on function of an expression product(s) such as aprotein(s), the degree of association with a disease, illness, orcondition, pathway analysis such as pathways listed in kyotoencyclopedia of genes and genomes (KEGG) database, literature evidence,or any combination thereof. Each factor may be given the same or adifferent weight in the determination and based on the determination, ascore may be generated.

The SSO druggability index may be determined based at least in part onfactors including e.g., an ability to identify unique and/or specificsplice correcting molecules (e.g., oligo sequence(s)) using AI such asmachine learning algorithms, a presence or absence of a strong enhancedcros slinking and immunoprecipitation (eCLIP) peak(s) mapped to theidentified target (e.g., an exon(s)), a presence or absence of a diseasespecific expression of an isoform(s) as compared to the genotype-tissueexpression (GTEx) normal data, or any combination thereof. Each factormay be given the same or a different weight in the determination and ascore may be generated based on the determination.

In cases in which a refined list of candidate targets is generated,candidate targets comprised in the list may be subject to additionalanalysis or processing steps. For example, splicing events associatedwith at least a subset of the candidate targets may be subjected to anevaluation process. The evaluation process may evaluate for expressionat various levels, for example, at the RNA level, at a protein level, orboth. The evaluation process may confirm differential isoform expressionin samples from different diseases (or subtypes thereof), illnesses, orconditions. Upon confirmation, the candidate targets may be selected andused for further development of therapeutics. In some cases, theselected targets comprise one or more genes. Non-limiting examples ofthe one or more genes may comprise NEDD4L (ENV2), MAP3K7 (ENV3), NFYA(ENV11), ESYT2 (ENV21), MARK2 (ENV18), ST7 (ENV19), ARVCF (ENV22), SYTL2(ENV17), R3HDM1 (ENV23), COL4A3BP (ENV9), TANGO2 (ENV6), SEPT9 (ENV15),ROBO1 (ENV4), FAM122B (ENV5), CD47 (ENV13), LSR (ENV20), PBX1 (ENV16),EPB41 (ENV14), ADAM15 (ENV7), EPB41L1 (ENV8), ABI1 (ENV10), FLNB (ENV1),CTNND1 (ENV12), GPR160 (ENV24), ITGB3BP (ENV25), INCENP (ENV26), DENND1B(ENV27), CA12 (ENV28), or any combination thereof.

Modulation of Targets using various Modalities

In some aspects of the present disclosure, methods and systems formodulating a splicing target(s) are provided. The modulation maycomprise modulating a splicing event(s) associated with a target (e.g.,a gene). The modulation may comprise promoting or facilitating a spliceswitching. For example, the modulation may comprise switching pathogenicisoforms to non-pathogenic isoforms.

The modulation may comprise the use of one or more compositions ormolecules which may interact specifically with (e.g., hybridize) atarget so as to control or alter splicing of the target or regulateexpression of the target at the RNA level, protein level or both. Thecompositions or molecules may be targeted to any element or combinationof elements (e.g., one or more genomic regions within a target) thatregulate splicing, including such as the 3 ‘splice site, the 5’ splicesite, the branch point, the polypyrimidine tract, exonic splicingenhancers, exonic splicing silencers, intronic splicing enhancers,intronic splicing silencers, or any combination thereof.

The compositions or molecules may comprise e.g., small molecules,polymers (natural or synthetic), nucleotide sequences such asoligonucleotides or RNAs, a therapeutic agent(s), cells such as CAR-Tcells, a protein such as an antibody, or any combination thereof.

The compositions or molecules may be admixed, encapsulated, conjugated,or otherwise associated with other molecules, molecule structures, ormixtures of compounds, for example liposomes, receptor targetedmolecules, oral, rectal, topical or other formulation, for assisting inuptake, distribution, and/or absorption.

The compositions or molecules may be applied in vivo or ex vivo. Toachieve target-specific, or disease-specific targeting, the compositionsor molecules may be added at a certain concentration. For example, thecompositions or molecules may have a concentration that is less than orequal to about 5 micromolar (μM), 4 μM, 3μM, 2 μM, 1 μM, 900 nanomolar(nM), 800 nM, 700 nM, 650 nM, 600 nM, 550 nM, 500 nM, 450 nM, 400 nM,350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, 50 nM, 10 nM, or less.The concentration may be greater than or equal to about 1 nM, 10 nM, 50nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900nM, or more. In some cases, the concentration may fall between any twoof the values discussed above, for example, about 370 nM or 420 nM.

In some cases, the compositions or molecules comprise oligonucleotides.The oligonucleotides may comprise any number of nucleotides ornucleotide residues, for example, greater than or equal to about 5, 10,12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46,48, 50, 55, 60 nucleotides or nucleotide residues, or more. In somecases, the oligonucleotides may comprise less than or equal to about 50,45, 40, 35, 30, 29, 27, 25, 24, 23, 22, 21, 19, 18, 17, 16, 13, 10, 8, 6nucleotides or nucleotide residues, or less. In some cases, the numberof nucleotides or nucleotide residues comprised in the oligonucleotidesmay fall between any of the values described above, for example, about16 (16-mer), 17 (17-mer), 18 (18-mer), 19 (19-mer), 20 (20-mer), 21(16-mer), or 22 (22-mer). In some cases, the oligonucleotides compriseDNA molecules, RNA molecules, or a combination thereof.

In some cases, the oligonucleotides comprise antisense oligonucleotides.The antisense oligonucleotides may be DNA and/or RNA oligos which arecomplementary to a given sequence, which given sequence may be a regionwithin a target gene.

The oligonucleotides may be prepared using various technologies such assolid phase synthesis, the phosphorothioates and/or alkylatedderivatives. The nucleotides or nucleotide residues comprised in theoligonucleotides may comprise natural, unmodified nucleotides (e.g.,cytosine, guanine, adenine, uracil or thymidine), modified nucleotides,or any combination thereof. In some cases, modified nucleotides or basesare used. The modification may be designed to enhance binding affinity.The modification may comprise chemical modifications. The modificationmay comprise backbone modifications, sugar ring modifications, or acombination thereof. The sugar ring modifications may comprise 2′-sugarmodifications. As an example, an oligonucleotide of the presentdisclosure may comprise a phosphothioate-modified backbone and/or ribosesugar modified to contain methoxy ethane at 2′-position (2′MOE). Theoligonucleotides comprising modified nucleotides or bases may notactivate RNase H. In some cases, one or more (e.g., at least about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40,45, or more) of the inter-nucleotide bridging phosphate residues aremodified phosphates, such as methyl phosphonates, methylphosphonothioates, phosphoromorpholidates, phosphoropiperazidates,phosphoroamidates, or any combination thereof. In some cases, one ormore (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 35, 40, 45, or more) of the nucleotides orbases comprise a 2′-alkyl moiety (e.g., C1-C4 alkyl, linear or branched,saturated or unsaturated including e.g., methyl, ethyl, ethenyl, propyl,1-propenyl, 2-propenyl, isopropyl, or combination or derivativethereof).

In some cases, the compositions or molecules comprise small molecules.The small molecules may comprise a broad range of chemical compoundsthat can switch the isoforms of the above-mentioned targets either atthe pre-mRNA level or protein level. These compounds may be identifiedthrough high-throughput screening approaches using chemical libraries,wherein addition of a compound or a combination of compounds can inducean isoform switch or modulate (e.g., inhibit or enhance) the biologicalactivity of a specific isoform of one or several of the genes (e.g.,genes mentioned above or described elsewhere herein) either at the levelof RNA or protein or both.

Application

The systems and methods of the present disclosure can be used fordetermining or identifying a novel splicing event(s) or a target (e.g.,a gene) to which the novel splicing event is associated with. The novelsplicing event(s) may be statistically significant or specific to one ormore given types or subtypes of diseases, illnesses or conditions. Toidentify the novel splicing events, the methods and systems of thepresent disclosure may receive data from one or more databases, publicand/or private, which data may comprise biologically relevant data withrespect to the types or subtypes of diseases, illnesses or conditionswhich are under investigation. The data may be analyzed, processed orannotated. The data analysis, processing, and/or annotation may beconducted using machine learning algorithms. The machine learning may bea supervised learning, an unsupervised learning, or a combinationthereof. The algorithm may be a trained algorithm. The algorithm may betrained using a training set. The training set may comprise trainingsamples. The training samples may be cell lines from certain diseases,illnesses, or conditions; samples obtained from subjects having certaindiseases, illnesses, or conditions; controls including positive and/ornegative controls; or any combination thereof.

The data analysis, processing, and/or annotation may generate a list ofcandidate targets which may potentially be used for therapeuticdevelopment. Candidate targets comprised in the list may be subjected tofurther screening process or analyses. Splicing of the candidate targetsmay be evaluated or validated. The evaluation or validation of thecandidate targets may yield a refined list of targets which may besubjected to further therapeutic development.

Splicing of individual targets comprised in the refined list may beusing compositions or molecules. The splicing may be modulated topromote switching of pathogenic isoforms to non-pathogenic isoforms. Thecompositions or molecules may be designed to target a select region or acombination of select regions within a target to achieve adisease-specific targeting. In some cases, the compositions or moleculesare designed to modulate the splicing of two or more (e.g., at least 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more) different targets.Compositions or molecules targeting different targets may be usedsequentially, or simultaneously.

In some aspects of the present disclosure, methods and systems forproviding treatment to a subject having or suspected to have a disease,illness, or condition are provided. The methods and systems may compriseobtaining a sample from the subject having or suspected to have adisease, illness, or condition. Biologically relevant data (e.g., DNA,RNA-seq data) may be derived or extracted from the sample. Thebiologically relevant data may be screened or processed to remove anydata unrelated to genome(s) or transcriptome(s). The processed data maybe subjected to one or more data analysis, processing or annotationprocesses which may identify one or more novel splicing eventsstatistically significant or specific to the disease, illness, orcondition the subject has or suspected to have. The splicing eventsidentified may be further analyzed or filtered using one or moreparameters or filtering criteria, which may generate a final list ofsplicing events and targets associated therewith for the treatment.

Upon identification of the targets, the systems and methods may furthercomprise administering a therapeutically effective amount ofcompositions or molecules to the subject having or suspected to have thedisease, illness, or condition. The administration may be conductedwithin a given time period. The subject may be monitored, and the amountof the compositions or molecules administered to the subject may beadjusted depending upon, the monitoring results. Additionally, themonitoring may comprise obtaining one or more samples from the subjectwhile the subject is under treatment. The one or more samples may beanalyzed or tested to determine if the treatment is effective or not. Ifa treatment is determined to be ineffective, the treatment may be ceasedand/or a different treatment (e.g., administering a different type ofcompositions or molecules) may be provided.

EXAMPLES Example 1 Identification of Alternatively Spliced Transcriptsin Triple Negative Breast Cancer (TNBC) and Therapeutics to Correct theSplicing Change

Breast cancer is the most commonly diagnosed cancer and the secondleading cause of cancer mortality in women, with nearly 30% of primarydisease diagnoses that result in metastatic breast cancer. One of thechallenges in breast cancer treatment is to overcome its largeheterogeneity and distinct cancer subtypes that may demand differentialtreatments including chemotherapy, hormonal therapy, and human epidermalgrowth factor receptor 2 (Her2-) targeted therapy (depending on thesubtype). However, a significant number of patients may developresistance to current standard of care therapies. This stresses the needfor identification of novel targets and development of alternativetherapies for complete disease remission.

Splicing errors can be a source of coding variation in breast cancer.Aberrant splicing of several genes may occur even without DNA mutationsor epigenetic changes due to mis-regulated expression of splicingfactors in breast cancer. Multiple studies have indicated the oncogenicrole of core splicing factors such as SRSF1, SRS F2, ESRP1, RBFOX1, etc.in breast cancer. For example, overexpression of SRSF1 may promotetransformation of non-cancerous breast epithelial cells. Additionally,it has been suggested that spliceosomal components may be particularlyessential factors in TNBC subtype, and the TNBC tumors sometimes showdependency on these factors. As an example, FIG. 1 shows an oncoprintsummary of recurring genomic aberration and transcriptional changes forsplicing associated RNA binding proteins in the Cancer Genome Atlas(TCGA) breast cancer TNBC subtype patient samples.

Additionally, splice site mutations that result in expression ofalternative isoforms have been reported in key breast cancer genes suchas ESR1 encoding estrogen receptor alpha rendering resistance to firstline drugs such as Tamoxifen in ER positive breast cancers.Mis-regulation of splicing factors have been shown to contribute toepithelial to mesenchymal switch by the production of mesenchymalisoforms of critical genes such as CD44 and FGFR2, thereby promotingtumor progression and metastasis. Given the suboptimal treatment optionsavailable for TNBC patients and the widespread splicing errors observedin TNBC patient RNA-seq data, disease specific alternative splicing canbe a source of actionable candidates that can be therapeuticallytargeted.

Systems of the present disclosure can be used to discover recurrentsplicing changes in TNBC patient RNA-seq and design modalities such asantisense oligonucleotides that target the specific isoforms in order topromote splice-switching to achieve a therapeutic benefit. As discussedabove or elsewhere herein, the systems may comprise the SpliceCore®software platform described in International Patent Application No.WO2019/226804, which has been incorporated herein by reference in itsentirety. In order to discover splicing changes that occur in TNBCsubtypes, RNA-seq data from luminal subtype patients and TNBC subtypepatients from TCGA breast cancer datasets are compared using theSpliceCore® software platform. In addition, RNA-sequencing intriplicates on breast cancer cell lines is performed. Two representativeluminal cell lines (i.e., MCF7, T47D) and two representative TNBC Bsubtype cell lines (i.e., HS578T, BT549) and one TNBC A subtype cellline (i.e., MDA-MB 468) are used. A flowchart of the SpliceCore®analysis of the TCGA and the cell line RNA seq data is illustrated inFIG. 2.

Comparison of the splicing changes between luminal breast cancer andbasal breast cancer from TCGA and the cell lines may independentlyresult in an identification of splicing changes that are distinct toTCGA (12,860 changes) and changes that are distinct to cell lines (944changes) (FIG. 3). Among those changes, there are about 274 splicingchanges that are identified in both TCGA and cell lines (FIG. 3). These274 splicing changes are considered candidates for target selection andmay be subject to further analysis. The analysis may be prioritizedbased on a number of parameters. The parameters (or buckets) forcandidate selection may serve as diversified target selection criteria,which may include e.g., a splicing index, a disease index, a therapeuticindex, a functional index, a splice-switching oligonucleotide (SSO)druggability index or any combination thereof. Example selectioncriteria and results are shown in FIG. 17. The figure shows arepresentative illustration of candidate selection scoring matrix basedon different parameters described above.

The splicing index can score for the splicing change (dPSI) in a givencase and a control, consistency, reproducibility of a given event inpatient datasets, and recurrence of a given event in multiple diseasedatasets and absent in normal datasets. The disease index can score forimpact of the splicing change on protein function (i.e.,“Splicelmpact™”), disease association (integrated through Open Targetscores), pathway analysis (KEGG), and literature evidence. The SSOdruggability index can score for the ability to identify unique andspecific splice correcting oligo sequence using machine learning (i.e.,“SpliceLearn™ scores”), presence of strong eCLIP peaks mapped to theidentified exons, and disease specific expression of the isoform(comparison with GTex normal data).

FIG. 18 reveals the identification of biologically relevant targets forthe treatment of leukemia as described herein. About 1178 RNA-seqdatasets from Acute Myeloid Leukemia (AML) patients obtained from theLeucegene consortium were analyzed to identify potential therapeutictargets. Different approaches were used to analyze alternative splicingevents including variance assessment (selection of strongest splicingchanges above a cutoff), reproducibility (selection for splicing changesrepeatedly observed in biological replicates), cross-validation(splicing changes confirmed in independent dataset(s)), and SpliceCore®(software platform described in International Patent Application No.WO2019/226804, which has been incorporated herein by reference in itsentirety). For each approach, the top 30 gene candidates were selectedand the gene candidates that were also known to be connected to AMLpathogenesis using records from OpenTargets (a public-privatepartnership using genomics data for drug target identification backed byGSK, Sanofi, Biogen, Takeda, Celgene, EMBL-EBI and Sanger Institute). Asshown in FIG. 18, 23 of the top 30 candidates identified by SpliceCorewere known to be connected to AML. The other approaches identified fewcandidates known to be connected to AML: the variance approachidentified 10 targets; the reproducibility approach identified 8targets; and the cros 5-validation approach identified 8 targets.

In an exemplary application of the selection criteria in FIG. 17, thealternative splicing index is determined by observing one or morealternative splicing event(s)/change(s) in in-house cell lines andpublic BRCA TCGA RNA-seq data; the therapeutic index is determined byconfirming that the one or more alternative splicing event(s)/change(s)is/are disease-specific and is/are not found in normal breast tissuesusing public GTEx RNA-seq; the functional index is determined by notingthat the score(s) for the one or more alternative splicingevent(s)/change(s) generated by Splicelmpact (software platformdescribed in International Patent Application No. WO2019/226804, whichhas been incorporated herein by reference in its entirety) aresignificantly disruptive; and the druggable index is determined by usingSpliceLearn (software platform described in International PatentApplication No. WO2019/226804, which has been incorporated herein byreference in its entirety) to predict that the one or more alternativesplicing event(s)/change(s) is a drug target. In some cases, the drugtarget is an SSO modulatory target.

In an another exemplary application of the selection criteria in FIG.17, the alternative splicing index is determined by observing one ormore alternative splicing event(s)/change(s) in in-house organoids andpublic BRCA TCGA RNA-seq from the Metabrick dataset; the therapeuticindex is determined by confirming that the one or more alternativesplicing event(s)/change(s) is/are disease-specific and is/are not foundin various post-mortem tissues including liver, heart, muscle and/orkidney, using public GTEx RNA-seq; the functional index is determined bynoting that the one or more alternative splicing event(s)/change(s)occur in one or more genes with high BRCA-association scores estimatedusing OpenTargets; and the druggable index is determined by confirmingthat binding of one or more oncogenic splicing factors to the one ormore target genes with the one or more alternative splicingevent(s)/change(s) using CLIP-seq data. In some cases, the one or moretarget genes may be blocked by ASO based in the selection criteriaanalyses.

In an another exemplary application of the selection criteria in FIG.17, the alternative splicing index is determined by observing one ormore alternative splicing event(s)/change(s) in in-house cell lines andlicensed RNA-seq from a partner; the therapeutic index is determined byconfirming that the one or more alternative splicing event(s)/change(s)is/are disease-specific and is/are not found in normal tissues frompartner RNA-seq; the functional index is determined by confirming thatthe one or more alternative splicing event(s)/change(s) are functionallyrelated breast cancer using public literature; and the druggable indexis determined by confirming that one or more alternative splicingevent(s)/change(s) occurs in one or more genes that is/are known to besmall molecule protein target(s).

Based on one or more of the above-mentioned filtering criteria orparameters, a total of 28 candidates whose splice changes may besignificant in TNBC subtype (Table 1—List of TNBC specific top scoringsplicing events and their corresponding gene names) are selected. Thesecandidates' splicing events are subsequently subjected to an evaluationfor expression at the level of RNA through PCR in experimental modelssuch as cell lines, primary cells, tissues, organoids, PDX tumors,patient tissue material, body fluids, etc. Wherever antibodies areavailable, splicing isoforms may also be evaluated for proteinexpression. Hybridization methods such as RNA-FISH can also be used tovalidate the specific isoform expression in tumor tissue sections.

TABLE 1 Gene ENV TXDBID (HUGO) Code CA-18-58335477-58335537.2267.0NEDD4L ENV2 CA-6-90544551-90544632.1 MAP3K7 ENV3CA-6-41080810-41080897.1 NFYA ENV11 CA-7-158752780-158752843.1 ESYT2ENV21 CA-11-63903985-63904147.1 MARK2 ENV18 CA-7-117134123-117134192.1ST7 ENV19 CA-22-19971215-19971335.1 ARVCF ENV22CA-11-85717482-85717530.1 SYTL2 ENV17 CA-2-135641535-135641604.2 R3HDM1ENV23 CA-5-75399309-75399387.1 COL4A3BP ENV9 CA-22-20053436-20053551.3TANGO2 ENV6 CA-17-77307140-77307197.5 SEPT9 ENV15CA-3-78647628-78647655.1 ROBO1 ENV4 CA-X-134772142-134772283.1 FAM122BENV5 CA-3-58141857-58141929.1 FLNB ENV1 CA-3-108050577-108050602.2 CD47ENV13 CA-1-29058588-29058645.2 EPB41 ENV14 CA-1-164820071-164820184.1PBX1 ENV16 CA-19-35262545-35262692.1 LSR ENV20CA-1-155061417-155061489.4 ADAM15 ENV7 CA-20-36209487-36209898.2 EPB41L1ENV8 CA-10-26755654-26755741.1 ABI1 ENV10 CA-11-57791493-57791673.2CTNND1 ENV12 CA-3-170082616-170082758.1 GPR160 ENV24CA-1-63447564-63447614.1 ITGB3BP ENV25 CA-11-62141499-62141511.1 INCENPENV26 CA-1-197647054-197647114.1 DENND1B ENV27 CA-15-63328097-63328130.1CA12 ENV28

First, reverse transcription polymerase chain reaction (RT-PCR) isperformed on selected candidates from the list of Table 1 to confirm thedifferential isoform expression in luminal versus the basal cell lines.Representative PCRs are shown in FIG. 4 where specific expression of thelong or the short isoform is enriched in TNBC cell lines versus luminalcell lines. Further, for a select group of candidates, western blotanalysis is also performed to verify the protein expression, and therepresentative western blot images for those candidates are shown inFIG. 5, which also shows differential isoform expression in proteinlysates extracted from luminal and basal cell lines.

Next, specific candidates are focused on to test to see if they can beused as a good therapeutic target for the development therapeuticcompounds. NEDD4L is suggested by the SpliceCore software platform asone of the top candidates and has shown the strongest dPSI change inTCGA data and very high reproducibility, along with known cancerassociation in a key signaling pathway (i.e., TGFbeta). By studying theimpact of the observed splicing changes on protein function, it isdetermined that the skipping isoform (short isoform) enriched in TNBCsubtype lacks a short loop region next to the WW domain which may beresponsible for protein-protein interaction. The loop contains aThreonine residue that may undergo post-translational modification by akinase, which can phosphorylate NEDD4L to maintain the homeostasis ofTGFbeta signaling. The TNBC cancer-specific loss of the loop throughalternative splicing may deregulate the signaling cascade leading totumor progression. Additionally, it is observed that breast cancerpatients expressing the inclusion isoform of NEDD4L have a betteroverall survival compared to the breast cancer patients that have theexpression of the skipped isoform (FIG. 6). Further analyses of thesubtype stratified data from TCGA have shown that the NEDD4L-skippingisoform is significantly enriched in TNBC subtype compared to normalbreast or luminal or HER2 subtypes of breast cancer. This difference hasbeen observed only at the level of alternative splicing and there isonly a modest difference in the total RNA expression of NEDD4L acrossthese subtypes (FIG. 7).

By using the SpliceCore® software platform and a module calledSpliceLearn, a machine-learning-based (ML-based) approach is used topredict nucleotide sequences with high likelihoods of promoting asplicing switch if blocked using a molecule (e.g., an oligonucleotide).These sequences are scored, and rank-ordered for every exon trio on thecandidate list. Additional scoring criteria may include the RBP bindingpeaks which can be obtained from ENCODE eCLIP-seq data and/or in-housegenerated eCLIP-seq data for splicing regulatory proteins including butnot limited to RBFOX2, TDP-43, HNRNPL.

Next, a list of k-mer sequences can be generated that span across thehigh scoring regions within the exon trio and may further be filteredbased on SSO specificity, repeat motifs, and off-target effects, andsecondary structure (FIG. 8). The top 5 oligos are chemicallysynthesized and may contain phosphothioate-modified backbone and/orribose sugar uniformly modified to contain methoxy ethane in 2′ position(2′MOE). Purified oligonucleotides can be subjected to functional assaysin breast cancer cell lines.

For NEDD4L, 5 different sequences (GCTGGCTTTGTCTGGATAGG (SEQ ID NO: 3),GTGGGTTTCAGGGATTCTGA (SEQ ID NO: 1), TCTCACGTCACCTGCCTTAC (SEQ ID NO:4), AGCGCTGCCACAGCAGTGGG (SEQ ID NO: 5),CCCTGATTCAGACAGCAGGG (SEQ ID NO:2)) are tested in total, and 2 of those sequences are found to promotethe inclusion of the middle exon significantly. GTGGGTTTCAGGGATTCTGA(SEQ ID NO: 1) (SSO2-2) is shown to promote an average of 40% inclusionratio in 3 out of 4 experiments, and (SSO2-5) CCCTGATTCAGACAGCAGGG (SEQID NO: 2) is shown to promote an average of 30% inclusion ratio in 4 outof 4 experiments (FIG. 9).

Dosage response experiments are performed to evaluate the LC50 value forthe SSO compounds in 2 breast cancer cell lines—i.e., the MCF7 (luminal)and MDA-MB-231 (TNBC) cell lines. Transfection of the SSO compounds showa dose responsive loss of viability in the MDA-MB-231 cells and not inthe MCF7 cells. The optimal dosing concentration in cell lines is foundto be between 370 nM-420 nM where >50% of the cell death has beenobserved. The cell viability can be evaluated by measuring themitochondrial ATP flux using the Celltitre glow assay. The meanluminescence can be converted to percentage of viable cells afternormalizing to control untransfected cells. The dose response curve forboth the SSO on two different cell lines is shown in FIGS. 10A-10B.

The criticality of alternative splicing events for TNMC tumors are alsoshown in FIG. 11, FIG. 12, FIG. 13 and FIG. 14. The alternative splicingevents may be associated with one or more genes as described above orelsewhere herein, e.g., genes comprising NEDD4L (ENV2), MAP3K7 (ENV3),NFYA (ENV11), ESYT2 (ENV21), MARK2 (ENV18), ST7 (ENV19), ARVCF (ENV22),SYTL2 (ENV17), R3HDM1 (ENV23), COL4A3BP (ENV9), TANGO2 (ENV6), SEPT9(ENV15), ROBO1 (ENV4), FAM122B (ENV5), CD47 (ENV13), LSR (ENV20), PBX1(ENV16), EPB41 (ENV14), ADAM15 (ENV7), EPB41L1 (ENV8), ABI1 (ENV10),FLNB (ENV1), CTNND1 (ENV12), GPR160 (ENV24), ITGB3BP (ENV25), INCENP(ENV26), DENND1B (ENV27), CA12 (ENV28), or a combination thereof.Survival analysis of TCGA BRCA patients containing long and shortisoforms for candidates is conducted with results illustrated in FIG. 15and FIG. 16, respectively. The candidates may be one or more genes asdescribed above or elsewhere herein, e.g., genes comprising NEDD4L(ENV2), MAP3K7 (ENV3), NFYA (ENV11), ESYT2 (ENV21), MARK2 (ENV18), ST7(ENV19), ARVCF (ENV22), SYTL2 (ENV17), R3HDM1 (ENV23), COL4A3BP (ENV9),TANGO2 (ENV6), SEPT9 (ENV15), ROBO1 (ENV4), FAM122B (ENV5), CD47(ENV13), LSR (ENV20), PBX1 (ENV 16), EPB41 (ENV14), ADAM (ENV7), EPB41L1(ENV8), ABI1 (ENV10), FLNB (ENV1), CTNND1 (ENV12), GPR160 (ENV24),ITGB3BP (ENV25), INCENP (ENV26), DENND1B (ENV27), CA12 (ENV28), or acombination thereof. The analysis shows significant different in overallsurvival in patients expressing either of the isoforms.

Thus, the above results show that TNBC subtype can be vulnerable tosplicing changes. Using the software platform of the present disclosure,reproducible and high impact splicing changes can be identified andvalidated in RNA-seq datasets from patient samples. The candidateslisted can potentially serve as a therapeutic target for TNBC breastcancer. The platform has also designed and nominated oligonucleotidesequences that can promote splice switching when targeted usingantisense oligos. The platform-designed oligos are experimentallyvalidated for NEDD4L using uniformly modified 2′MOE oligonucleotidechemistry. The NEDD4L alternative splicing is a splicing event specificto TNBC subtype of breast cancer. Targeting NEDD4L isoform switchingusing modalities such as antisense oligonucleotides exhibits selectiveviability loss in TNBC cells specifically in a dose responsive manner.As such, NEDD4L splicing can be an actionable event to developtherapeutic to treat TNBC patients.

It shall be understood that although the above example is related toTNBC RNA-seq datasets, the NEDD4L and other candidate splicing events asdiscussed above or elsewhere herein can also be important in other solidor hematological malignancies, as well as in neurological or metabolicdiseases. One or more of the splicing changes can be responsible forpathogenesis or progression of such diseases, disorders, or conditions,and the therapeutic targeting of the present disclosure can be appliedto such diseases, disorders, or conditions.

Alternatively or additionally, the splicing targets can be modulatedusing modalities including, but not limited to, small molecules, GAPMERoligonucleotides, siRNAs, CAR-T cells, or any combination thereof toachieve disease-specific targeting. For example, some of thedisease-specific splicing events that have been identified can open upgrooves for small molecule binding. In such case, small molecules can bedesigned to target the region that is created because of a splicingchange. In another example, splicing changes of the membrane boundproteins can display altered surface epitopes which can be specificallytargeted using antibodies. The SpliceCore software platform, and themethods as described above and elsewhere herein, can be used to analyze,design, and develop multimodal therapeutic targets for a wide range ofdisease indications.

Example 2 Target-Specific Anti-Sense Oligonucleotides (ASOs)

As provided above and elsewhere herein, the ASOs can be identified basedon exon position and SpliceLearn^(TM) features such as RNA bindingprotein. The ASOs can be used for splice switching experiments topromote exon inclusion in the target candidates provided herein. In somecases, chemically-modified ASOs may be synthesized based on the ASOsidentified. For example, one or more chemical modifications can beintroduced in one or more ASOs. The chemical modification can comprise aphosphorothioate backbone modification and/or 2′-O-(2 Methoxyethyl)ribose modification (2′MOE) (modification of the ribose sugar).Sequences of the ASOs may be used for one or more ex vivo experiments onbreast cancer cell lines to determine the effect of the ASOs on spliceswitching of the target gene candidates.

A select group of the ASOs may be used for further in vitro and in vivoexperiments and preclinical studies. In some instances, the specificsplice switching event can be identified to be strongly associated withtriple negative breast cancer (TNBC). In some embodiments, the ASOs mayhave potent splice switching effects with less toxicity. In some cases,the ASOs can be used in preclinical studies and/or in the therapeuticdevelopment of targeting of cancer-specific genes in patients. Forexample, an ASO can be used in the therapeutic development in thetargeting of TNBC breast cancer patients by inducing a splice switchthat can potentially have an anti-tumor effect.

Tables 2-8 list example target-specific oligonucleotide sequences ofvariable sequence lengths which may be used to induce an isoform switchor modulate (e.g., inhibit or enhance) the biological activity of aspecific isoform of one or several of the genes described above orelsewhere herein (e.g., genes comprising one or more of NEDD4L (ENV2),MAP3K7 (ENV3), NFYA (ENV11), ESYT2 (ENV21), MARK2 (ENV18), ST7 (ENV19),ARVCF (ENV22), SYTL2 (ENV17), R3HDM1 (ENV23), COL4A3BP (ENV9), TANGO2(ENV6), SEPT9 (ENV15), ROBO1 (ENV4), FAM122B (ENV5), CD47 (ENV13), LSR(ENV20), PBX1 (ENV16), EPB41 (ENV14), ADAM15 (ENV7), EPB41L1 (ENV8),ABI1 (ENV10), FLNB (ENV1), CTNND1 (ENV12), GPR160 (ENV24), ITGB3BP(ENV25), INCENP (ENV26), DENND1B (ENV27), CA12 (ENV28).

In some cases, oligonucleotide sequences comprised in a table arespecific for a single target. In some cases, oligonucleotide sequencescomprised in a table are specific for more than one target. In somecases, oligonucleotide sequences comprised in more than one tables arespecific for a single target. For example, oligonucleotide sequencescomprised in Tables 2-8 may be specific for a single target. The targetmay be a gene selected from genes described above or elsewhere herein.

TABLE 2 16-mer target-specific ASOs SEQ CHR START END STRAND kmerSEQUENCE ID NO: chr3 58141828 58141843 +/− 16 CCCAACTAATCTCCAT 6 chr358141829 58141844 +/− 16 CCAACTAATCTCCATT 7 chr3 58141830 58141845 +/−16 CAACTAATCTCCATTT 8 chr3 58141831 58141846 +/− 16 AACTAATCTCCATTTG 9chr3 58141832 58141847 +/− 16 ACTAATCTCCATTTGC 10 chr3 58141833 58141848+/− 16 CTAATCTCCATTTGCC 11 chr3 58141834 58141849 +/− 16TAATCTCCATTTGCCA 12 chr3 58141835 58141850 +/− 16 AATCTCCATTTGCCAC 13chr3 58141836 58141851 +/− 16 ATCTCCATTTGCCACT 14 chr3 58141837 58141852+/− 16 TCTCCATTTGCCACTG 15 chr3 58141838 58141853 +/− 16CTCCATTTGCCACTGA 16 chr3 58141839 58141854 +/− 16 TCCATTTGCCACTGAC 17chr3 58141840 58141855 +/− 16 CCATTTGCCACTGACC 18 chr3 58141841 58141856+/− 16 CATTTGCCACTGACCA 19 chr3 58141842 58141857 +/− 16ATTTGCCACTGACCAG 20 chr3 58141843 58141858 +/− 16 TTTGCCACTGACCAGG 21chr3 58141844 58141859 +/− 16 TTGCCACTGACCAGGC 22 chr3 58141845 58141860+/− 16 TGCCACTGACCAGGCC 23 chr3 58141846 58141861 +/− 16GCCACTGACCAGGCCA 24 chr3 58141847 58141862 +/− 16 CCACTGACCAGGCCAC 25chr3 58141848 58141863 +/− 16 CACTGACCAGGCCACA 26 chr3 58141849 58141864+/− 16 ACTGACCAGGCCACAG 27 chr3 58141850 58141865 +/− 16CTGACCAGGCCACAGA 28 chr3 58141851 58141866 +/− 16 TGACCAGGCCACAGAT 29chr3 58141852 58141867 +/− 16 GACCAGGCCACAGATG 30 chr3 58141853 58141868+/− 16 ACCAGGCCACAGATGG 31 chr3 58141854 58141869 +/− 16CCAGGCCACAGATGGG 32 chr3 58141855 58141870 +/− 16 CAGGCCACAGATGGGG 33chr3 58141856 58141871 +/− 16 AGGCCACAGATGGGGA 34 chr3 58141857 58141872+/− 16 GGCCACAGATGGGGAA 35 chr3 58141858 58141873 +/− 16GCCACAGATGGGGAAG 36 chr3 58141859 58141874 +/− 16 CCACAGATGGGGAAGT 37chr3 58141860 58141875 +/− 16 CACAGATGGGGAAGTC 38 chr3 58141861 58141876+/− 16 ACAGATGGGGAAGTCA 39 chr3 58141862 58141877 +/− 16CAGATGGGGAAGTCAC 40 chr3 58141863 58141878 +/− 16 AGATGGGGAAGTCACA 41chr3 58141864 58141879 +/− 16 GATGGGGAAGTCACAG 42 chr3 58141865 58141880+/− 16 ATGGGGAAGTCACAGC 43 chr3 58141866 58141881 +/− 16TGGGGAAGTCACAGCC 44 chr3 58141867 58141882 +/− 16 GGGGAAGTCACAGCCG 45chr3 58141868 58141883 +/− 16 GGGAAGTCACAGCCGT 46 chr3 58141869 58141884+/− 16 GGAAGTCACAGCCGTG 47 chr3 58141870 58141885 +/− 16GAAGTCACAGCCGTGG 48 chr3 58141871 58141886 +/− 16 AAGTCACAGCCGTGGA 49chr3 58141872 58141887 +/− 16 AGTCACAGCCGTGGAG 50 chr3 58141873 58141888+/− 16 GTCACAGCCGTGGAGG 51 chr3 58141874 58141889 +/− 16TCACAGCCGTGGAGGA 52 chr3 58141875 58141890 +/− 16 CACAGCCGTGGAGGAG 53chr3 58141876 58141891 +/− 16 ACAGCCGTGGAGGAGG 54 chr3 58141877 58141892+/− 16 CAGCCGTGGAGGAGGC 55 chr3 58141878 58141893 +/− 16AGCCGTGGAGGAGGCA 56 chr3 58141879 58141894 +/− 16 GCCGTGGAGGAGGCAC 57chr3 58141880 58141895 +/− 16 CCGTGGAGGAGGCACC 58 chr3 58141881 58141896+/− 16 CGTGGAGGAGGCACCG 59 chr3 58141882 58141897 +/− 16GTGGAGGAGGCACCGG 60 chr3 58141883 58141898 +/− 16 TGGAGGAGGCACCGGT 61chr3 58141884 58141899 +/− 16 GGAGGAGGCACCGGTA 62 chr3 58141885 58141900+/− 16 GAGGAGGCACCGGTAA 63 chr3 58141886 58141901 +/− 16AGGAGGCACCGGTAAA 64 chr3 58141887 58141902 +/− 16 GGAGGCACCGGTAAAT 65chr3 58141888 58141903 +/− 16 GAGGCACCGGTAAATG 66 chr3 58141889 58141904+/− 16 AGGCACCGGTAAATGC 67 chr3 58141890 58141905 +/− 16GGCACCGGTAAATGCA 68 chr3 58141891 58141906 +/− 16 GCACCGGTAAATGCAT 69chr3 58141892 58141907 +/− 16 CACCGGTAAATGCATG 70 chr3 58141893 58141908+/− 16 ACCGGTAAATGCATGT 71 chr3 58141894 58141909 +/− 16CCGGTAAATGCATGTC 72 chr3 58141895 58141910 +/− 16 CGGTAAATGCATGTCC 73chr3 58141896 58141911 +/− 16 GGTAAATGCATGTCCC 74 chr3 58141897 58141912+/− 16 GTAAATGCATGTCCCC 75 chr3 58141898 58141913 +/− 16TAAATGCATGTCCCCC 76 chr3 58141899 58141914 +/− 16 AAATGCATGTCCCCCT 77chr3 58141900 58141915 +/− 16 AATGCATGTCCCCCTG 78 chr3 58141901 58141916+/− 16 ATGCATGTCCCCCTGG 79 chr3 58141902 58141917 +/− 16TGCATGTCCCCCTGGA 80 chr3 58141903 58141918 +/− 16 GCATGTCCCCCTGGAT 81chr3 58141904 58141919 +/− 16 CATGTCCCCCTGGATT 82 chr3 58141905 58141920+/− 16 ATGTCCCCCTGGATTC 83 chr3 58141906 58141921 +/− 16TGTCCCCCTGGATTCA 84 chr3 58141907 58141922 +/− 16 GTCCCCCTGGATTCAG 85chr3 58141908 58141923 +/− 16 TCCCCCTGGATTCAGG 86 chr3 58141909 58141924+/− 16 CCCCCTGGATTCAGGC 87 chr3 58141910 58141925 +/− 16CCCCTGGATTCAGGCC 88 chr3 58141911 58141926 +/− 16 CCCTGGATTCAGGCCC 89chr3 58141912 58141927 +/− 16 CCTGGATTCAGGCCCT 90 chr3 58141913 58141928+/− 16 CTGGATTCAGGCCCTG 91 chr3 58141914 58141929 +/− 16TGGATTCAGGCCCTGG 92 chr3 58141915 58141930 +/− 16 GGATTCAGGCCCTGGG 93chr3 58141916 58141931 +/− 16 GATTCAGGCCCTGGGT 94 chr3 58141917 58141932+/− 16 ATTCAGGCCCTGGGTA 95 chr3 58141918 58141933 +/− 16TTCAGGCCCTGGGTAC 96 chr3 58141919 58141934 +/− 16 TCAGGCCCTGGGTACA 97chr3 58141920 58141935 +/− 16 CAGGCCCTGGGTACAA 98 chr3 58141921 58141936+/− 16 AGGCCCTGGGTACAAT 99 chr3 58141922 58141937 +/− 16GGCCCTGGGTACAATT 100 chr3 58141923 58141938 +/− 16 GCCCTGGGTACAATTT 101chr3 58141924 58141939 +/− 16 CCCTGGGTACAATTTT 102 chr3 5814192558141940 +/− 16 CCTGGGTACAATTTTG 103 chr3 58141926 58141941 +/− 16CTGGGTACAATTTTGG 104 chr3 58141927 58141942 +/− 16 TGGGTACAATTTTGGT 105chr3 58141928 58141943 +/− 16 GGGTACAATTTTGGTT 106 chr3 5814192958141944 +/− 16 GGTACAATTTTGGTTT 107 chr3 58141930 58141945 +/− 16GTACAATTTTGGTTTT 108 chr3 58141931 58141946 +/− 16 TACAATTTTGGTTTTT 109chr3 58141932 58141947 +/− 16 ACAATTTTGGTTTTTT 110 chr3 5814193358141948 +/− 16 CAATTTTGGTTTTTTC 111 chr3 58141934 58141949 +/− 16AATTTTGGTTTTTTCC 112 chr3 58141935 58141950 +/− 16 ATTTTGGTTTTTTCCT 113chr3 58141936 58141951 +/− 16 TTTTGGTTTTTTCCTT 114 chr3 5814193758141952 +/− 16 TTTGGTTTTTTCCTTT 115 chr3 58141938 58141953 +/− 16TTGGTTTTTTCCTTTT 116 chr3 58141939 58141954 +/− 16 TGGTTTTTTCCTTTTT 117chr3 58141940 58141955 +/− 16 GGTTTTTTCCTTTTTG 118 chr3 5814194158141956 +/− 16 GTTTTTTCCTTTTTGT 119 chr3 58141942 58141957 +/− 16TTTTTTCCTTTTTGTG 120 chr3 58141943 58141958 +/− 16 TTTTTCCTTTTTGTGT 121chr3 58141944 58141959 +/− 16 TTTTCCTTTTTGTGTT 122 chr3 5814194558141960 +/− 16 TTTCCTTTTTGTGTTT 123 chr3 58141946 58141961 +/− 16TTCCTTTTTGTGTTTC 124 chr3 58141947 58141962 +/− 16 TCCTTTTTGTGTTTCT 125chr3 58141948 58141963 +/− 16 CCTTTTTGTGTTTCTG 126 chr3 5814194958141964 +/− 16 CTTTTTGTGTTTCTGT 127 chr3 58141950 58141965 +/− 16TTTTTGTGTTTCTGTG 128 chr3 58141951 58141966 +/− 16 TTTTGTGTTTCTGTGT 129chr3 58141952 58141967 +/− 16 TTTGTGTTTCTGTGTT 130 chr3 5814195358141968 +/− 16 TTGTGTTTCTGTGTTT 131 chr3 58141954 58141969 +/− 16TGTGTTTCTGTGTTTA 132 chr3 58141955 58141970 +/− 16 GTGTTTCTGTGTTTAC 133chr3 58141956 58141971 +/− 16 TGTTTCTGTGTTTACT 134 chr3 5814195758141972 +/− 16 GTTTCTGTGTTTACTC 135 chr3 58141958 58141973 +/− 16TTTCTGTGTTTACTCA 136 chr3 58141959 58141974 +/− 16 TTCTGTGTTTACTCAG 137chr3 58141960 58141975 +/− 16 TCTGTGTTTACTCAGC 138 chr3 5814196158141976 +/− 16 CTGTGTTTACTCAGCC 139 chr3 58141962 58141977 +/− 16TGTGTTTACTCAGCCT 140 chr3 58141963 58141978 +/− 16 GTGTTTACTCAGCCTT 141chr3 58141964 58141979 +/− 16 TGTTTACTCAGCCTTC 142 chr3 5814196558141980 +/− 16 GTTTACTCAGCCTTCA 143 chr3 58141966 58141981 +/− 16TTTACTCAGCCTTCAT 144 chr3 58141967 58141982 +/− 16 TTACTCAGCCTTCATT 145chr3 58141968 58141983 +/− 16 TACTCAGCCTTCATTT 146 chr3 5814196958141984 +/− 16 ACTCAGCCTTCATTTC 147 chr3 58141970 58141985 +/− 16CTCAGCCTTCATTTCA 148 chr3 58141971 58141986 +/− 16 TCAGCCTTCATTTCAG 149chr3 58141972 58141987 +/− 16 CAGCCTTCATTTCAGA 150 chr3 5814197358141988 +/− 16 AGCCTTCATTTCAGAA 151 chr3 58141974 58141989 +/− 16GCCTTCATTTCAGAAA 152 chr3 58141975 58141990 +/− 16 CCTTCATTTCAGAAAA 153chr3 58141976 58141991 +/− 16 CTTCATTTCAGAAAAT 154 chr3 5814197758141992 +/− 16 TTCATTTCAGAAAATC 155 chr3 58141978 58141993 +/− 16TCATTTCAGAAAATCT 156 chr3 58141979 58141994 +/− 16 CATTTCAGAAAATCTG 157chr3 58141980 58141995 +/− 16 ATTTCAGAAAATCTGC 158 chr3 5814198158141996 +/− 16 TTTCAGAAAATCTGCC 159 chr3 58141982 58141997 +/− 16TTCAGAAAATCTGCCA 160 chr3 58141983 58141998 +/− 16 TCAGAAAATCTGCCAT 161chr3 58141984 58141999 +/− 16 CAGAAAATCTGCCATC 162 chr3 5814198558142000 +/− 16 AGAAAATCTGCCATCT 163 chr3 58141986 58142001 +/− 16GAAAATCTGCCATCTG 164 chr3 58141987 58142002 +/− 16 AAAATCTGCCATCTGC 165chr3 58141988 58142003 +/− 16 AAATCTGCCATCTGCT 166 chr3 5814198958142004 +/− 16 AATCTGCCATCTGCTT 167 chr3 58141990 58142005 +/− 16ATCTGCCATCTGCTTC 168 chr3 58141991 58142006 +/− 16 TCTGCCATCTGCTTCT 169chr3 58141992 58142007 +/− 16 CTGCCATCTGCTTCTG 170 chr3 5814199358142008 +/− 16 TGCCATCTGCTTCTGG 171 chr3 58141994 58142009 +/− 16GCCATCTGCTTCTGGG 172 chr3 58141995 58142010 +/− 16 CCATCTGCTTCTGGGA 173chr3 58141996 58142011 +/− 16 CATCTGCTTCTGGGAT 174 chr3 5814199758142012 +/− 16 ATCTGCTTCTGGGATT 175 chr3 58141998 58142013 +/− 16TCTGCTTCTGGGATTG 176 chr3 58141999 58142014 +/− 16 CTGCTTCTGGGATTGC 177chr3 58142000 58142015 +/− 16 TGCTTCTGGGATTGCT 178 chr3 5814200158142016 +/− 16 GCTTCTGGGATTGCTT 179 chr3 58142002 58142017 +/− 16CTTCTGGGATTGCTTA 180 chr3 58142003 58142018 +/− 16 TTCTGGGATTGCTTAA 181chr3 58142004 58142019 +/− 16 TCTGGGATTGCTTAAG 182 chr3 5814200558142020 +/− 16 CTGGGATTGCTTAAGC 183 chr3 58142006 58142021 +/− 16TGGGATTGCTTAAGCC 184 chr3 58142007 58142022 +/− 16 GGGATTGCTTAAGCCC 185chr3 58142008 58142023 +/− 16 GGATTGCTTAAGCCCT 186 chr3 5814200958142024 +/− 16 GATTGCTTAAGCCCTG 187 chr3 58142010 58142025 +/− 16ATTGCTTAAGCCCTGT 188 chr3 58142011 58142026 +/− 16 TTGCTTAAGCCCTGTG 189chr3 58142012 58142027 +/− 16 TGCTTAAGCCCTGTGG 190 chr3 5814201358142028 +/− 16 GCTTAAGCCCTGTGGG 191 chr3 58142014 58142029 +/− 16CTTAAGCCCTGTGGGT 192 chr3 58142015 58142030 +/− 16 TTAAGCCCTGTGGGTG 193chr3 58142016 58142031 +/− 16 TAAGCCCTGTGGGTGT 194 chr3 5814201758142032 +/− 16 AAGCCCTGTGGGTGTC 195 chr3 58142018 58142033 +/− 16AGCCCTGTGGGTGTCC 196 chr3 58142019 58142034 +/− 16 GCCCTGTGGGTGTCCT 197chr3 58142020 58142035 +/− 16 CCCTGTGGGTGTCCTG 198 chr3 5814202158142036 +/− 16 CCTGTGGGTGTCCTGG 199 chr3 58142022 58142037 +/− 16CTGTGGGTGTCCTGGT 200 chr3 58142023 58142038 +/− 16 TGTGGGTGTCCTGGTC 201chr3 58142024 58142039 +/− 16 GTGGGTGTCCTGGTCA 202 chr3 5814202558142040 +/− 16 TGGGTGTCCTGGTCAT 203 chr3 58142026 58142041 +/− 16GGGTGTCCTGGTCATT 204 chr3 58142027 58142042 +/− 16 GGTGTCCTGGTCATTG 205chr3 58142028 58142043 +/− 16 GTGTCCTGGTCATTGG 206 chr3 5814202958142044 +/− 16 TGTCCTGGTCATTGGT 207

TABLE 3 17-mer target-specific ASOs SEQ ID CHR START END STRAND kmerSEQUENCE NO: chr3 58141828 58141844 +/− 17 CCCAACTAATCTCCATT 208 chr358141829 58141845 +/− 17 CCAACTAATCTCCATTT 209 chr3 58141830 58141846+/− 17 CAACTAATCTCCATTTG 210 chr3 58141831 58141847 +/− 17AACTAATCTCCATTTGC 211 chr3 58141832 58141848 +/− 17 ACTAATCTCCATTTGCC212 chr3 58141833 58141849 +/− 17 CTAATCTCCATTTGCCA 213 chr3 5814183458141850 +/− 17 TAATCTCCATTTGCCAC 214 chr3 58141835 58141851 +/− 17AATCTCCATTTGCCACT 215 chr3 58141836 58141852 +/− 17 ATCTCCATTTGCCACTG216 chr3 58141837 58141853 +/− 17 TCTCCATTTGCCACTGA 217 chr3 5814183858141854 +/− 17 CTCCATTTGCCACTGAC 218 chr3 58141839 58141855 +/− 17TCCATTTGCCACTGACC 219 chr3 58141840 58141856 +/− 17 CCATTTGCCACTGACCA220 chr3 58141841 58141857 +/− 17 CATTTGCCACTGACCAG 221 chr3 5814184258141858 +/− 17 ATTTGCCACTGACCAGG 222 chr3 58141843 58141859 +/− 17TTTGCCACTGACCAGGC 223 chr3 58141844 58141860 +/− 17 TTGCCACTGACCAGGCC224 chr3 58141845 58141861 +/− 17 TGCCACTGACCAGGCCA 225 chr3 5814184658141862 +/− 17 GCCACTGACCAGGCCAC 226 chr3 58141847 58141863 +/− 17CCACTGACCAGGCCACA 227 chr3 58141848 58141864 +/− 17 CACTGACCAGGCCACAG228 chr3 58141849 58141865 +/− 17 ACTGACCAGGCCACAGA 229 chr3 5814185058141866 +/− 17 CTGACCAGGCCACAGAT 230 chr3 58141851 58141867 +/− 17TGACCAGGCCACAGATG 231 chr3 58141852 58141868 +/− 17 GACCAGGCCACAGATGG232 chr3 58141853 58141869 +/− 17 ACCAGGCCACAGATGGG 233 chr3 5814185458141870 +/− 17 CCAGGCCACAGATGGGG 234 chr3 58141855 58141871 +/− 17CAGGCCACAGATGGGGA 235 chr3 58141856 58141872 +/− 17 AGGCCACAGATGGGGAA236 chr3 58141857 58141873 +/− 17 GGCCACAGATGGGGAAG 237 chr3 5814185858141874 +/− 17 GCCACAGATGGGGAAGT 238 chr3 58141859 58141875 +/− 17CCACAGATGGGGAAGTC 239 chr3 58141860 58141876 +/− 17 CACAGATGGGGAAGTCA240 chr3 58141861 58141877 +/− 17 ACAGATGGGGAAGTCAC 241 chr3 5814186258141878 +/− 17 CAGATGGGGAAGTCACA 242 chr3 58141863 58141879 +/− 17AGATGGGGAAGTCACAG 243 chr3 58141864 58141880 +/− 17 GATGGGGAAGTCACAGC244 chr3 58141865 58141881 +/− 17 ATGGGGAAGTCACAGCC 245 chr3 5814186658141882 +/− 17 TGGGGAAGTCACAGCCG 246 chr3 58141867 58141883 +/− 17GGGGAAGTCACAGCCGT 247 chr3 58141868 58141884 +/− 17 GGGAAGTCACAGCCGTG248 chr3 58141869 58141885 +/− 17 GGAAGTCACAGCCGTGG 249 chr3 5814187058141886 +/− 17 GAAGTCACAGCCGTGGA 250 chr3 58141871 58141887 +/− 17AAGTCACAGCCGTGGAG 251 chr3 58141872 58141888 +/− 17 AGTCACAGCCGTGGAGG252 chr3 58141873 58141889 +/− 17 GTCACAGCCGTGGAGGA 253 chr3 5814187458141890 +/− 17 TCACAGCCGTGGAGGAG 254 chr3 58141875 58141891 +/− 17CACAGCCGTGGAGGAGG 255 chr3 58141876 58141892 +/− 17 ACAGCCGTGGAGGAGGC256 chr3 58141877 58141893 +/− 17 CAGCCGTGGAGGAGGCA 257 chr3 5814187858141894 +/− 17 AGCCGTGGAGGAGGCAC 258 chr3 58141879 58141895 +/− 17GCCGTGGAGGAGGCACC 259 chr3 58141880 58141896 +/− 17 CCGTGGAGGAGGCACCG260 chr3 58141881 58141897 +/− 17 CGTGGAGGAGGCACCGG 261 chr3 5814188258141898 +/− 17 GTGGAGGAGGCACCGGT 262 chr3 58141883 58141899 +/− 17TGGAGGAGGCACCGGTA 263 chr3 58141884 58141900 +/− 17 GGAGGAGGCACCGGTAA264 chr3 58141885 58141901 +/− 17 GAGGAGGCACCGGTAAA 265 chr3 5814188658141902 +/− 17 AGGAGGCACCGGTAAAT 266 chr3 58141887 58141903 +/− 17GGAGGCACCGGTAAATG 267 chr3 58141888 58141904 +/− 17 GAGGCACCGGTAAATGC268 chr3 58141889 58141905 +/− 17 AGGCACCGGTAAATGCA 269 chr3 5814189058141906 +/− 17 GGCACCGGTAAATGCAT 270 chr3 58141891 58141907 +/− 17GCACCGGTAAATGCATG 271 chr3 58141892 58141908 +/− 17 CACCGGTAAATGCATGT272 chr3 58141893 58141909 +/− 17 ACCGGTAAATGCATGTC 273 chr3 5814189458141910 +/− 17 CCGGTAAATGCATGTCC 274 chr3 58141895 58141911 +/− 17CGGTAAATGCATGTCCC 275 chr3 58141896 58141912 +/− 17 GGTAAATGCATGTCCCC276 chr3 58141897 58141913 +/− 17 GTAAATGCATGTCCCCC 277 chr3 5814189858141914 +/− 17 TAAATGCATGTCCCCCT 278 chr3 58141899 58141915 +/− 17AAATGCATGTCCCCCTG 279 chr3 58141900 58141916 +/− 17 AATGCATGTCCCCCTGG280 chr3 58141901 58141917 +/− 17 ATGCATGTCCCCCTGGA 281 chr3 5814190258141918 +/− 17 TGCATGTCCCCCTGGAT 282 chr3 58141903 58141919 +/− 17GCATGTCCCCCTGGATT 283 chr3 58141904 58141920 +/− 17 CATGTCCCCCTGGATTC284 chr3 58141905 58141921 +/− 17 ATGTCCCCCTGGATTCA 285 chr3 5814190658141922 +/− 17 TGTCCCCCTGGATTCAG 286 chr3 58141907 58141923 +/− 17GTCCCCCTGGATTCAGG 287 chr3 58141908 58141924 +/− 17 TCCCCCTGGATTCAGGC288 chr3 58141909 58141925 +/− 17 CCCCCTGGATTCAGGCC 289 chr3 5814191058141926 +/− 17 CCCCTGGATTCAGGCCC 290 chr3 58141911 58141927 +/− 17CCCTGGATTCAGGCCCT 291 chr3 58141912 58141928 +/− 17 CCTGGATTCAGGCCCTG292 chr3 58141913 58141929 +/− 17 CTGGATTCAGGCCCTGG 293 chr3 5814191458141930 +/− 17 TGGATTCAGGCCCTGGG 294 chr3 58141915 58141931 +/− 17GGATTCAGGCCCTGGGT 295 chr3 58141916 58141932 +/− 17 GATTCAGGCCCTGGGTA296 chr3 58141917 58141933 +/− 17 ATTCAGGCCCTGGGTAC 297 chr3 5814191858141934 +/− 17 TTCAGGCCCTGGGTACA 298 chr3 58141919 58141935 +/− 17TCAGGCCCTGGGTACAA 299 chr3 58141920 58141936 +/− 17 CAGGCCCTGGGTACAAT300 chr3 58141921 58141937 +/− 17 AGGCCCTGGGTACAATT 301 chr3 5814192258141938 +/− 17 GGCCCTGGGTACAATTT 302 chr3 58141923 58141939 +/− 17GCCCTGGGTACAATTTT 303 chr3 58141924 58141940 +/− 17 CCCTGGGTACAATTTTG304 chr3 58141925 58141941 +/− 17 CCTGGGTACAATTTTGG 305 chr3 5814192658141942 +/− 17 CTGGGTACAATTTTGGT 306 chr3 58141927 58141943 +/− 17TGGGTACAATTTTGGTT 307 chr3 58141928 58141944 +/− 17 GGGTACAATTTTGGTTT308 chr3 58141929 58141945 +/− 17 GGTACAATTTTGGTTTT 309 chr3 5814193058141946 +/− 17 GTACAATTTTGGTTTTT 310 chr3 58141931 58141947 +/− 17TACAATTTTGGTTTTTT 311 chr3 58141932 58141948 +/− 17 ACAATTTTGGTTTTTTC312 chr3 58141933 58141949 +/− 17 CAATTTTGGTTTTTTCC 313 chr3 5814193458141950 +/− 17 AATTTTGGTTTTTTCCT 314 chr3 58141935 58141951 +/− 17ATTTTGGTTTTTTCCTT 315 chr3 58141936 58141952 +/− 17 TTTTGGTTTTTTCCTTT316 chr3 58141937 58141953 +/− 17 TTTGGTTTTTTCCTTTT 317 chr3 5814193858141954 +/− 17 TTGGTTTTTTCCTTTTT 318 chr3 58141939 58141955 +/− 17TGGTTTTTTCCTTTTTG 319 chr3 58141940 58141956 +/− 17 GGTTTTTTCCTTTTTGT320 chr3 58141941 58141957 +/− 17 GTTTTTTCCTTTTTGTG 321 chr3 5814194258141958 +/− 17 TTTTTTCCTTTTTGTGT 322 chr3 58141943 58141959 +/− 17TTTTTCCTTTTTGTGTT 323 chr3 58141944 58141960 +/− 17 TTTTCCTTTTTGTGTTT324 chr3 58141945 58141961 +/− 17 TTTCCTTTTTGTGTTTC 325 chr3 5814194658141962 +/− 17 TTCCTTTTTGTGTTTCT 326 chr3 58141947 58141963 +/− 17TCCTTTTTGTGTTTCTG 327 chr3 58141948 58141964 +/− 17 CCTTTTTGTGTTTCTGT328 chr3 58141949 58141965 +/− 17 CTTTTTGTGTTTCTGTG 329 chr3 5814195058141966 +/− 17 TTTTTGTGTTTCTGTGT 330 chr3 58141951 58141967 +/− 17TTTTGTGTTTCTGTGTT 331 chr3 58141952 58141968 +/− 17 TTTGTGTTTCTGTGTTT332 chr3 58141953 58141969 +/− 17 TTGTGTTTCTGTGTTTA 333 chr3 5814195458141970 +/− 17 TGTGTTTCTGTGTTTAC 334 chr3 58141955 58141971 +/− 17GTGTTTCTGTGTTTACT 335 chr3 58141956 58141972 +/− 17 TGTTTCTGTGTTTACTC336 chr3 58141957 58141973 +/− 17 GTTTCTGTGTTTACTCA 337 chr3 5814195858141974 +/− 17 TTTCTGTGTTTACTCAG 338 chr3 58141959 58141975 +/− 17TTCTGTGTTTACTCAGC 339 chr3 58141960 58141976 +/− 17 TCTGTGTTTACTCAGCC340 chr3 58141961 58141977 +/− 17 CTGTGTTTACTCAGCCT 341 chr3 5814196258141978 +/− 17 TGTGTTTACTCAGCCTT 342 chr3 58141963 58141979 +/− 17GTGTTTACTCAGCCTTC 343 chr3 58141964 58141980 +/− 17 TGTTTACTCAGCCTTCA344 chr3 58141965 58141981 +/− 17 GTTTACTCAGCCTTCAT 345 chr3 5814196658141982 +/− 17 TTTACTCAGCCTTCATT 346 chr3 58141967 58141983 +/− 17TTACTCAGCCTTCATTT 347 chr3 58141968 58141984 +/− 17 TACTCAGCCTTCATTTC348 chr3 58141969 58141985 +/− 17 ACTCAGCCTTCATTTCA 349 chr3 5814197058141986 +/− 17 CTCAGCCTTCATTTCAG 350 chr3 58141971 58141987 +/− 17TCAGCCTTCATTTCAGA 351 chr3 58141972 58141988 +/− 17 CAGCCTTCATTTCAGAA352 chr3 58141973 58141989 +/− 17 AGCCTTCATTTCAGAAA 353 chr3 5814197458141990 +/− 17 GCCTTCATTTCAGAAAA 354 chr3 58141975 58141991 +/− 17CCTTCATTTCAGAAAAT 355 chr3 58141976 58141992 +/− 17 CTTCATTTCAGAAAATC356 chr3 58141977 58141993 +/− 17 TTCATTTCAGAAAATCT 357 chr3 5814197858141994 +/− 17 TCATTTCAGAAAATCTG 358 chr3 58141979 58141995 +/− 17CATTTCAGAAAATCTGC 359 chr3 58141980 58141996 +/− 17 ATTTCAGAAAATCTGCC360 chr3 58141981 58141997 +/− 17 TTTCAGAAAATCTGCCA 361 chr3 5814198258141998 +/− 17 TTCAGAAAATCTGCCAT 362 chr3 58141983 58141999 +/− 17TCAGAAAATCTGCCATC 363 chr3 58141984 58142000 +/− 17 CAGAAAATCTGCCATCT364 chr3 58141985 58142001 +/− 17 AGAAAATCTGCCATCTG 365 chr3 5814198658142002 +/− 17 GAAAATCTGCCATCTGC 366 chr3 58141987 58142003 +/− 17AAAATCTGCCATCTGCT 367 chr3 58141988 58142004 +/− 17 AAATCTGCCATCTGCTT368 chr3 58141989 58142005 +/− 17 AATCTGCCATCTGCTTC 369 chr3 5814199058142006 +/− 17 ATCTGCCATCTGCTTCT 370 chr3 58141991 58142007 +/− 17TCTGCCATCTGCTTCTG 371 chr3 58141992 58142008 +/− 17 CTGCCATCTGCTTCTGG372 chr3 58141993 58142009 +/− 17 TGCCATCTGCTTCTGGG 373 chr3 5814199458142010 +/− 17 GCCATCTGCTTCTGGGA 374 chr3 58141995 58142011 +/− 17CCATCTGCTTCTGGGAT 375 chr3 58141996 58142012 +/− 17 CATCTGCTTCTGGGATT376 chr3 58141997 58142013 +/− 17 ATCTGCTTCTGGGATTG 377 chr3 5814199858142014 +/− 17 TCTGCTTCTGGGATTGC 378 chr3 58141999 58142015 +/− 17CTGCTTCTGGGATTGCT 379 chr3 58142000 58142016 +/− 17 TGCTTCTGGGATTGCTT380 chr3 58142001 58142017 +/− 17 GCTTCTGGGATTGCTTA 381 chr3 5814200258142018 +/− 17 CTTCTGGGATTGCTTAA 382 chr3 58142003 58142019 +/− 17TTCTGGGATTGCTTAAG 383 chr3 58142004 58142020 +/− 17 TCTGGGATTGCTTAAGC384 chr3 58142005 58142021 +/− 17 CTGGGATTGCTTAAGCC 385 chr3 5814200658142022 +/− 17 TGGGATTGCTTAAGCCC 386 chr3 58142007 58142023 +/− 17GGGATTGCTTAAGCCCT 387 chr3 58142008 58142024 +/− 17 GGATTGCTTAAGCCCTG388 chr3 58142009 58142025 +/− 17 GATTGCTTAAGCCCTGT 389 chr3 5814201058142026 +/− 17 ATTGCTTAAGCCCTGTG 390 chr3 58142011 58142027 +/− 17TTGCTTAAGCCCTGTGG 391 chr3 58142012 58142028 +/− 17 TGCTTAAGCCCTGTGGG392 chr3 58142013 58142029 +/− 17 GCTTAAGCCCTGTGGGT 393 chr3 5814201458142030 +/− 17 CTTAAGCCCTGTGGGTG 394 chr3 58142015 58142031 +/− 17TTAAGCCCTGTGGGTGT 395 chr3 58142016 58142032 +/− 17 TAAGCCCTGTGGGTGTC396 chr3 58142017 58142033 +/− 17 AAGCCCTGTGGGTGTCC 397 chr3 5814201858142034 +/− 17 AGCCCTGTGGGTGTCCT 398 chr3 58142019 58142035 +/− 17GCCCTGTGGGTGTCCTG 399 chr3 58142020 58142036 +/− 17 CCCTGTGGGTGTCCTGG400 chr3 58142021 58142037 +/− 17 CCTGTGGGTGTCCTGGT 401 chr3 5814202258142038 +/− 17 CTGTGGGTGTCCTGGTC 402 chr3 58142023 58142039 +/− 17TGTGGGTGTCCTGGTCA 403 chr3 58142024 58142040 +/− 17 GTGGGTGTCCTGGTCAT404 chr3 58142025 58142041 +/− 17 TGGGTGTCCTGGTCATT 405 chr3 5814202658142042 +/− 17 GGGTGTCCTGGTCATTG 406 chr3 58142027 58142043 +/− 17GGTGTCCTGGTCATTGG 407 chr3 58142028 58142044 +/− 17 GTGTCCTGGTCATTGGT408

TABLE 4 18-mer target-specific ASOs SEQ ID CHR START END STRAND kmerSEQUENCE NO: chr3 58141828 58141845 +/− 18 CCCAACTAATCTCCATTT 409 chr358141829 58141846 +/− 18 CCAACTAATCTCCATTTG 410 chr3 58141830 58141847+/− 18 CAACTAATCTCCATTTGC 411 chr3 58141831 58141848 +/− 18AACTAATCTCCATTTGCC 412 chr3 58141832 58141849 +/− 18 ACTAATCTCCATTTGCCA413 chr3 58141833 58141850 +/− 18 CTAATCTCCATTTGCCAC 414 chr3 5814183458141851 +/− 18 TAATCTCCATTTGCCACT 415 chr3 58141835 58141852 +/− 18AATCTCCATTTGCCACTG 416 chr3 58141836 58141853 +/− 18 ATCTCCATTTGCCACTGA417 chr3 58141837 58141854 +/− 18 TCTCCATTTGCCACTGAC 418 chr3 5814183858141855 +/− 18 CTCCATTTGCCACTGACC 419 chr3 58141839 58141856 +/− 18TCCATTTGCCACTGACCA 420 chr3 58141840 58141857 +/− 18 CCATTTGCCACTGACCAG421 chr3 58141841 58141858 +/− 18 CATTTGCCACTGACCAGG 422 chr3 5814184258141859 +/− 18 ATTTGCCACTGACCAGGC 423 chr3 58141843 58141860 +/− 18TTTGCCACTGACCAGGCC 424 chr3 58141844 58141861 +/− 18 TTGCCACTGACCAGGCCA425 chr3 58141845 58141862 +/− 18 TGCCACTGACCAGGCCAC 426 chr3 5814184658141863 +/− 18 GCCACTGACCAGGCCACA 427 chr3 58141847 58141864 +/− 18CCACTGACCAGGCCACAG 428 chr3 58141848 58141865 +/− 18 CACTGACCAGGCCACAGA429 chr3 58141849 58141866 +/− 18 ACTGACCAGGCCACAGAT 430 chr3 5814185058141867 +/− 18 CTGACCAGGCCACAGATG 431 chr3 58141851 58141868 +/− 18TGACCAGGCCACAGATGG 432 chr3 58141852 58141869 +/− 18 GACCAGGCCACAGATGGG433 chr3 58141853 58141870 +/− 18 ACCAGGCCACAGATGGGG 434 chr3 5814185458141871 +/− 18 CCAGGCCACAGATGGGGA 435 chr3 58141855 58141872 +/− 18CAGGCCACAGATGGGGAA 436 chr3 58141856 58141873 +/− 18 AGGCCACAGATGGGGAAG437 chr3 58141857 58141874 +/− 18 GGCCACAGATGGGGAAGT 438 chr3 5814185858141875 +/− 18 GCCACAGATGGGGAAGTC 439 chr3 58141859 58141876 +/− 18CCACAGATGGGGAAGTCA 440 chr3 58141860 58141877 +/− 18 CACAGATGGGGAAGTCAC441 chr3 58141861 58141878 +/− 18 ACAGATGGGGAAGTCACA 442 chr3 5814186258141879 +/− 18 CAGATGGGGAAGTCACAG 443 chr3 58141863 58141880 +/− 18AGATGGGGAAGTCACAGC 444 chr3 58141864 58141881 +/− 18 GATGGGGAAGTCACAGCC445 chr3 58141865 58141882 +/− 18 ATGGGGAAGTCACAGCCG 446 chr3 5814186658141883 +/− 18 TGGGGAAGTCACAGCCGT 447 chr3 58141867 58141884 +/− 18GGGGAAGTCACAGCCGTG 448 chr3 58141868 58141885 +/− 18 GGGAAGTCACAGCCGTGG449 chr3 58141869 58141886 +/− 18 GGAAGTCACAGCCGTGGA 450 chr3 5814187058141887 +/− 18 GAAGTCACAGCCGTGGAG 451 chr3 58141871 58141888 +/− 18AAGTCACAGCCGTGGAGG 452 chr3 58141872 58141889 +/− 18 AGTCACAGCCGTGGAGGA453 chr3 58141873 58141890 +/− 18 GTCACAGCCGTGGAGGAG 454 chr3 5814187458141891 +/− 18 TCACAGCCGTGGAGGAGG 455 chr3 58141875 58141892 +/− 18CACAGCCGTGGAGGAGGC 456 chr3 58141876 58141893 +/− 18 ACAGCCGTGGAGGAGGCA457 chr3 58141877 58141894 +/− 18 CAGCCGTGGAGGAGGCAC 458 chr3 5814187858141895 +/− 18 AGCCGTGGAGGAGGCACC 459 chr3 58141879 58141896 +/− 18GCCGTGGAGGAGGCACCG 460 chr3 58141880 58141897 +/− 18 CCGTGGAGGAGGCACCGG461 chr3 58141881 58141898 +/− 18 CGTGGAGGAGGCACCGGT 462 chr3 5814188258141899 +/− 18 GTGGAGGAGGCACCGGTA 463 chr3 58141883 58141900 +/− 18TGGAGGAGGCACCGGTAA 464 chr3 58141884 58141901 +/− 18 GGAGGAGGCACCGGTAAA465 chr3 58141885 58141902 +/− 18 GAGGAGGCACCGGTAAAT 466 chr3 5814188658141903 +/− 18 AGGAGGCACCGGTAAATG 467 chr3 58141887 58141904 +/− 18GGAGGCACCGGTAAATGC 468 chr3 58141888 58141905 +/− 18 GAGGCACCGGTAAATGCA469 chr3 58141889 58141906 +/− 18 AGGCACCGGTAAATGCAT 470 chr3 5814189058141907 +/− 18 GGCACCGGTAAATGCATG 471 chr3 58141891 58141908 +/− 18GCACCGGTAAATGCATGT 472 chr3 58141892 58141909 +/− 18 CACCGGTAAATGCATGTC473 chr3 58141893 58141910 +/− 18 ACCGGTAAATGCATGTCC 474 chr3 5814189458141911 +/− 18 CCGGTAAATGCATGTCCC 475 chr3 58141895 58141912 +/− 18CGGTAAATGCATGTCCCC 476 chr3 58141896 58141913 +/− 18 GGTAAATGCATGTCCCCC477 chr3 58141897 58141914 +/− 18 GTAAATGCATGTCCCCCT 478 chr3 5814189858141915 +/− 18 TAAATGCATGTCCCCCTG 479 chr3 58141899 58141916 +/− 18AAATGCATGTCCCCCTGG 480 chr3 58141900 58141917 +/− 18 AATGCATGTCCCCCTGGA481 chr3 58141901 58141918 +/− 18 ATGCATGTCCCCCTGGAT 482 chr3 5814190258141919 +/− 18 TGCATGTCCCCCTGGATT 483 chr3 58141903 58141920 +/− 18GCATGTCCCCCTGGATTC 484 chr3 58141904 58141921 +/− 18 CATGTCCCCCTGGATTCA485 chr3 58141905 58141922 +/− 18 ATGTCCCCCTGGATTCAG 486 chr3 5814190658141923 +/− 18 TGTCCCCCTGGATTCAGG 487 chr3 58141907 58141924 +/− 18GTCCCCCTGGATTCAGGC 488 chr3 58141908 58141925 +/− 18 TCCCCCTGGATTCAGGCC489 chr3 58141909 58141926 +/− 18 CCCCCTGGATTCAGGCCC 490 chr3 5814191058141927 +/− 18 CCCCTGGATTCAGGCCCT 491 chr3 58141911 58141928 +/− 18CCCTGGATTCAGGCCCTG 492 chr3 58141912 58141929 +/− 18 CCTGGATTCAGGCCCTGG493 chr3 58141913 58141930 +/− 18 CTGGATTCAGGCCCTGGG 494 chr3 5814191458141931 +/− 18 TGGATTCAGGCCCTGGGT 495 chr3 58141915 58141932 +/− 18GGATTCAGGCCCTGGGTA 496 chr3 58141916 58141933 +/− 18 GATTCAGGCCCTGGGTAC497 chr3 58141917 58141934 +/− 18 ATTCAGGCCCTGGGTACA 498 chr3 5814191858141935 +/− 18 TTCAGGCCCTGGGTACAA 499 chr3 58141919 58141936 +/− 18TCAGGCCCTGGGTACAAT 500 chr3 58141920 58141937 +/− 18 CAGGCCCTGGGTACAATT501 chr3 58141921 58141938 +/− 18 AGGCCCTGGGTACAATTT 502 chr3 5814192258141939 +/− 18 GGCCCTGGGTACAATTTT 503 chr3 58141923 58141940 +/− 18GCCCTGGGTACAATTTTG 504 chr3 58141924 58141941 +/− 18 CCCTGGGTACAATTTTGG505 chr3 58141925 58141942 +/− 18 CCTGGGTACAATTTTGGT 506 chr3 5814192658141943 +/− 18 CTGGGTACAATTTTGGTT 507 chr3 58141927 58141944 +/− 18TGGGTACAATTTTGGTTT 508 chr3 58141928 58141945 +/− 18 GGGTACAATTTTGGTTTT509 chr3 58141929 58141946 +/− 18 GGTACAATTTTGGTTTTT 510 chr3 5814193058141947 +/− 18 GTACAATTTTGGTTTTTT 511 chr3 58141931 58141948 +/− 18TACAATTTTGGTTTTTTC 512 chr3 58141932 58141949 +/− 18 ACAATTTTGGTTTTTTCC513 chr3 58141933 58141950 +/− 18 CAATTTTGGTTTTTTCCT 514 chr3 5814193458141951 +/− 18 AATTTTGGTTTTTTCCTT 515 chr3 58141935 58141952 +/− 18ATTTTGGTTTTTTCCTTT 516 chr3 58141936 58141953 +/− 18 TTTTGGTTTTTTCCTTTT517 chr3 58141937 58141954 +/− 18 TTTGGTTTTTTCCTTTTT 518 chr3 5814193858141955 +/− 18 TTGGTTTTTTCCTTTTTG 519 chr3 58141939 58141956 +/− 18TGGTTTTTTCCTTTTTGT 520 chr3 58141940 58141957 +/− 18 GGTTTTTTCCTTTTTGTG521 chr3 58141941 58141958 +/− 18 GTTTTTTCCTTTTTGTGT 522 chr3 5814194258141959 +/− 18 TTTTTTCCTTTTTGTGTT 523 chr3 58141943 58141960 +/− 18TTTTTCCTTTTTGTGTTT 524 chr3 58141944 58141961 +/− 18 TTTTCCTTTTTGTGTTTC525 chr3 58141945 58141962 +/− 18 TTTCCTTTTTGTGTTTCT 526 chr3 5814194658141963 +/− 18 TTCCTTTTTGTGTTTCTG 527 chr3 58141947 58141964 +/− 18TCCTTTTTGTGTTTCTGT 528 chr3 58141948 58141965 +/− 18 CCTTTTTGTGTTTCTGTG529 chr3 58141949 58141966 +/− 18 CTTTTTGTGTTTCTGTGT 530 chr3 5814195058141967 +/− 18 TTTTTGTGTTTCTGTGTT 531 chr3 58141951 58141968 +/− 18TTTTGTGTTTCTGTGTTT 532 chr3 58141952 58141969 +/− 18 TTTGTGTTTCTGTGTTTA533 chr3 58141953 58141970 +/− 18 TTGTGTTTCTGTGTTTAC 534 chr3 5814195458141971 +/− 18 TGTGTTTCTGTGTTTACT 535 chr3 58141955 58141972 +/− 18GTGTTTCTGTGTTTACTC 536 chr3 58141956 58141973 +/− 18 TGTTTCTGTGTTTACTCA537 chr3 58141957 58141974 +/− 18 GTTTCTGTGTTTACTCAG 538 chr3 5814195858141975 +/− 18 TTTCTGTGTTTACTCAGC 539 chr3 58141959 58141976 +/− 18TTCTGTGTTTACTCAGCC 540 chr3 58141960 58141977 +/− 18 TCTGTGTTTACTCAGCCT541 chr3 58141961 58141978 +/− 18 CTGTGTTTACTCAGCCTT 542 chr3 5814196258141979 +/− 18 TGTGTTTACTCAGCCTTC 543 chr3 58141963 58141980 +/− 18GTGTTTACTCAGCCTTCA 544 chr3 58141964 58141981 +/− 18 TGTTTACTCAGCCTTCAT545 chr3 58141965 58141982 +/− 18 GTTTACTCAGCCTTCATT 546 chr3 5814196658141983 +/− 18 TTTACTCAGCCTTCATTT 547 chr3 58141967 58141984 +/− 18TTACTCAGCCTTCATTTC 548 chr3 58141968 58141985 +/− 18 TACTCAGCCTTCATTTCA549 chr3 58141969 58141986 +/− 18 ACTCAGCCTTCATTTCAG 550 chr3 5814197058141987 +/− 18 CTCAGCCTTCATTTCAGA 551 chr3 58141971 58141988 +/− 18TCAGCCTTCATTTCAGAA 552 chr3 58141972 58141989 +/− 18 CAGCCTTCATTTCAGAAA553 chr3 58141973 58141990 +/− 18 AGCCTTCATTTCAGAAAA 554 chr3 5814197458141991 +/− 18 GCCTTCATTTCAGAAAAT 555 chr3 58141975 58141992 +/− 18CCTTCATTTCAGAAAATC 556 chr3 58141976 58141993 +/− 18 CTTCATTTCAGAAAATCT557 chr3 58141977 58141994 +/− 18 TTCATTTCAGAAAATCTG 558 chr3 5814197858141995 +/− 18 TCATTTCAGAAAATCTGC 559 chr3 58141979 58141996 +/− 18CATTTCAGAAAATCTGCC 560 chr3 58141980 58141997 +/− 18 ATTTCAGAAAATCTGCCA561 chr3 58141981 58141998 +/− 18 TTTCAGAAAATCTGCCAT 562 chr3 5814198258141999 +/− 18 TTCAGAAAATCTGCCATC 563 chr3 58141983 58142000 +/− 18TCAGAAAATCTGCCATCT 564 chr3 58141984 58142001 +/− 18 CAGAAAATCTGCCATCTG565 chr3 58141985 58142002 +/− 18 AGAAAATCTGCCATCTGC 566 chr3 5814198658142003 +/− 18 GAAAATCTGCCATCTGCT 567 chr3 58141987 58142004 +/− 18AAAATCTGCCATCTGCTT 568 chr3 58141988 58142005 +/− 18 AAATCTGCCATCTGCTTC569 chr3 58141989 58142006 +/− 18 AATCTGCCATCTGCTTCT 570 chr3 5814199058142007 +/− 18 ATCTGCCATCTGCTTCTG 571 chr3 58141991 58142008 +/− 18TCTGCCATCTGCTTCTGG 572 chr3 58141992 58142009 +/− 18 CTGCCATCTGCTTCTGGG573 chr3 58141993 58142010 +/− 18 TGCCATCTGCTTCTGGGA 574 chr3 5814199458142011 +/− 18 GCCATCTGCTTCTGGGAT 575 chr3 58141995 58142012 +/− 18CCATCTGCTTCTGGGATT 576 chr3 58141996 58142013 +/− 18 CATCTGCTTCTGGGATTG577 chr3 58141997 58142014 +/− 18 ATCTGCTTCTGGGATTGC 578 chr3 5814199858142015 +/− 18 TCTGCTTCTGGGATTGCT 579 chr3 58141999 58142016 +/− 18CTGCTTCTGGGATTGCTT 580 chr3 58142000 58142017 +/− 18 TGCTTCTGGGATTGCTTA581 chr3 58142001 58142018 +/− 18 GCTTCTGGGATTGCTTAA 582 chr3 5814200258142019 +/− 18 CTTCTGGGATTGCTTAAG 583 chr3 58142003 58142020 +/− 18TTCTGGGATTGCTTAAGC 584 chr3 58142004 58142021 +/− 18 TCTGGGATTGCTTAAGCC585 chr3 58142005 58142022 +/− 18 CTGGGATTGCTTAAGCCC 586 chr3 5814200658142023 +/− 18 TGGGATTGCTTAAGCCCT 587 chr3 58142007 58142024 +/− 18GGGATTGCTTAAGCCCTG 588 chr3 58142008 58142025 +/− 18 GGATTGCTTAAGCCCTGT589 chr3 58142009 58142026 +/− 18 GATTGCTTAAGCCCTGTG 590 chr3 5814201058142027 +/− 18 ATTGCTTAAGCCCTGTGG 591 chr3 58142011 58142028 +/− 18TTGCTTAAGCCCTGTGGG 592 chr3 58142012 58142029 +/− 18 TGCTTAAGCCCTGTGGGT593 chr3 58142013 58142030 +/− 18 GCTTAAGCCCTGTGGGTG 594 chr3 5814201458142031 +/− 18 CTTAAGCCCTGTGGGTGT 595 chr3 58142015 58142032 +/− 18TTAAGCCCTGTGGGTGTC 596 chr3 58142016 58142033 +/− 18 TAAGCCCTGTGGGTGTCC597 chr3 58142017 58142034 +/− 18 AAGCCCTGTGGGTGTCCT 598 chr3 5814201858142035 +/− 18 AGCCCTGTGGGTGTCCTG 599 chr3 58142019 58142036 +/− 18GCCCTGTGGGTGTCCTGG 600 chr3 58142020 58142037 +/− 18 CCCTGTGGGTGTCCTGGT601 chr3 58142021 58142038 +/− 18 CCTGTGGGTGTCCTGGTC 602 chr3 5814202258142039 +/− 18 CTGTGGGTGTCCTGGTCA 603 chr3 58142023 58142040 +/− 18TGTGGGTGTCCTGGTCAT 604 chr3 58142024 58142041 +/− 18 GTGGGTGTCCTGGTCATT605 chr3 58142025 58142042 +/− 18 TGGGTGTCCTGGTCATTG 606 chr3 5814202658142043 +/− 18 GGGTGTCCTGGTCATTGG 607 chr3 58142027 58142044 +/− 18GGTGTCCTGGTCATTGGT 608

TABLE 5 19-mer target-specific ASOs SEQ ID CHR START END STRAND kmerSEQUENCE NO: chr3 58141828 58141846 +/− 19 CCCAACTAATCTCCATTTG 609 chr358141829 58141847 +/− 19 CCAACTAATCTCCATTTGC 610 chr3 58141830 58141848+/− 19 CAACTAATCTCCATTTGCC 611 chr3 58141831 58141849 +/− 19AACTAATCTCCATTTGCCA 612 chr3 58141832 58141850 +/− 19ACTAATCTCCATTTGCCAC 613 chr3 58141833 58141851 +/− 19CTAATCTCCATTTGCCACT 614 chr3 58141834 58141852 +/− 19TAATCTCCATTTGCCACTG 615 chr3 58141835 58141853 +/− 19AATCTCCATTTGCCACTGA 616 chr3 58141836 58141854 +/− 19ATCTCCATTTGCCACTGAC 617 chr3 58141837 58141855 +/− 19TCTCCATTTGCCACTGACC 618 chr3 58141838 58141856 +/− 19CTCCATTTGCCACTGACCA 619 chr3 58141839 58141857 +/− 19TCCATTTGCCACTGACCAG 620 chr3 58141840 58141858 +/− 19CCATTTGCCACTGACCAGG 621 chr3 58141841 58141859 +/− 19CATTTGCCACTGACCAGGC 622 chr3 58141842 58141860 +/− 19ATTTGCCACTGACCAGGCC 623 chr3 58141843 58141861 +/− 19TTTGCCACTGACCAGGCCA 624 chr3 58141844 58141862 +/− 19TTGCCACTGACCAGGCCAC 625 chr3 58141845 58141863 +/− 19TGCCACTGACCAGGCCACA 626 chr3 58141846 58141864 +/− 19GCCACTGACCAGGCCACAG 627 chr3 58141847 58141865 +/− 19CCACTGACCAGGCCACAGA 628 chr3 58141848 58141866 +/− 19CACTGACCAGGCCACAGAT 629 chr3 58141849 58141867 +/− 19ACTGACCAGGCCACAGATG 630 chr3 58141850 58141868 +/− 19CTGACCAGGCCACAGATGG 631 chr3 58141851 58141869 +/− 19TGACCAGGCCACAGATGGG 632 chr3 58141852 58141870 +/− 19GACCAGGCCACAGATGGGG 633 chr3 58141853 58141871 +/− 19ACCAGGCCACAGATGGGGA 634 chr3 58141854 58141872 +/− 19CCAGGCCACAGATGGGGAA 635 chr3 58141855 58141873 +/− 19CAGGCCACAGATGGGGAAG 636 chr3 58141856 58141874 +/− 19AGGCCACAGATGGGGAAGT 637 chr3 58141857 58141875 +/− 19GGCCACAGATGGGGAAGTC 638 chr3 58141858 58141876 +/− 19GCCACAGATGGGGAAGTCA 639 chr3 58141859 58141877 +/− 19CCACAGATGGGGAAGTCAC 640 chr3 58141860 58141878 +/− 19CACAGATGGGGAAGTCACA 641 chr3 58141861 58141879 +/− 19ACAGATGGGGAAGTCACAG 642 chr3 58141862 58141880 +/− 19CAGATGGGGAAGTCACAGC 643 chr3 58141863 58141881 +/− 19AGATGGGGAAGTCACAGCC 644 chr3 58141864 58141882 +/− 19GATGGGGAAGTCACAGCCG 645 chr3 58141865 58141883 +/− 19ATGGGGAAGTCACAGCCGT 646 chr3 58141866 58141884 +/− 19TGGGGAAGTCACAGCCGTG 647 chr3 58141867 58141885 +/− 19GGGGAAGTCACAGCCGTGG 648 chr3 58141868 58141886 +/− 19GGGAAGTCACAGCCGTGGA 649 chr3 58141869 58141887 +/− 19GGAAGTCACAGCCGTGGAG 650 chr3 58141870 58141888 +/− 19GAAGTCACAGCCGTGGAGG 651 chr3 58141871 58141889 +/− 19AAGTCACAGCCGTGGAGGA 652 chr3 58141872 58141890 +/− 19AGTCACAGCCGTGGAGGAG 653 chr3 58141873 58141891 +/− 19GTCACAGCCGTGGAGGAGG 654 chr3 58141874 58141892 +/− 19TCACAGCCGTGGAGGAGGC 655 chr3 58141875 58141893 +/− 19CACAGCCGTGGAGGAGGCA 656 chr3 58141876 58141894 +/− 19ACAGCCGTGGAGGAGGCAC 657 chr3 58141877 58141895 +/− 19CAGCCGTGGAGGAGGCACC 658 chr3 58141878 58141896 +/− 19AGCCGTGGAGGAGGCACCG 659 chr3 58141879 58141897 +/− 19GCCGTGGAGGAGGCACCGG 660 chr3 58141880 58141898 +/− 19CCGTGGAGGAGGCACCGGT 661 chr3 58141881 58141899 +/− 19CGTGGAGGAGGCACCGGTA 662 chr3 58141882 58141900 +/− 19GTGGAGGAGGCACCGGTAA 663 chr3 58141883 58141901 +/− 19TGGAGGAGGCACCGGTAAA 664 chr3 58141884 58141902 +/− 19GGAGGAGGCACCGGTAAAT 665 chr3 58141885 58141903 +/− 19GAGGAGGCACCGGTAAATG 666 chr3 58141886 58141904 +/− 19AGGAGGCACCGGTAAATGC 667 chr3 58141887 58141905 +/− 19GGAGGCACCGGTAAATGCA 668 chr3 58141888 58141906 +/− 19GAGGCACCGGTAAATGCAT 669 chr3 58141889 58141907 +/− 19AGGCACCGGTAAATGCATG 670 chr3 58141890 58141908 +/− 19GGCACCGGTAAATGCATGT 671 chr3 58141891 58141909 +/− 19GCACCGGTAAATGCATGTC 672 chr3 58141892 58141910 +/− 19CACCGGTAAATGCATGTCC 673 chr3 58141893 58141911 +/− 19ACCGGTAAATGCATGTCCC 674 chr3 58141894 58141912 +/− 19CCGGTAAATGCATGTCCCC 675 chr3 58141895 58141913 +/− 19CGGTAAATGCATGTCCCCC 676 chr3 58141896 58141914 +/− 19GGTAAATGCATGTCCCCCT 677 chr3 58141897 58141915 +/− 19GTAAATGCATGTCCCCCTG 678 chr3 58141898 58141916 +/− 19TAAATGCATGTCCCCCTGG 679 chr3 58141899 58141917 +/− 19AAATGCATGTCCCCCTGGA 680 chr3 58141900 58141918 +/− 19AATGCATGTCCCCCTGGAT 681 chr3 58141901 58141919 +/− 19ATGCATGTCCCCCTGGATT 682 chr3 58141902 58141920 +/− 19TGCATGTCCCCCTGGATTC 683 chr3 58141903 58141921 +/− 19GCATGTCCCCCTGGATTCA 684 chr3 58141904 58141922 +/− 19CATGTCCCCCTGGATTCAG 685 chr3 58141905 58141923 +/− 19ATGTCCCCCTGGATTCAGG 686 chr3 58141906 58141924 +/− 19TGTCCCCCTGGATTCAGGC 687 chr3 58141907 58141925 +/− 19GTCCCCCTGGATTCAGGCC 688 chr3 58141908 58141926 +/− 19TCCCCCTGGATTCAGGCCC 689 chr3 58141909 58141927 +/− 19CCCCCTGGATTCAGGCCCT 690 chr3 58141910 58141928 +/− 19CCCCTGGATTCAGGCCCTG 691 chr3 58141911 58141929 +/− 19CCCTGGATTCAGGCCCTGG 692 chr3 58141912 58141930 +/− 19CCTGGATTCAGGCCCTGGG 693 chr3 58141913 58141931 +/− 19CTGGATTCAGGCCCTGGGT 694 chr3 58141914 58141932 +/− 19TGGATTCAGGCCCTGGGTA 695 chr3 58141915 58141933 +/− 19GGATTCAGGCCCTGGGTAC 696 chr3 58141916 58141934 +/− 19GATTCAGGCCCTGGGTACA 697 chr3 58141917 58141935 +/− 19ATTCAGGCCCTGGGTACAA 698 chr3 58141918 58141936 +/− 19TTCAGGCCCTGGGTACAAT 699 chr3 58141919 58141937 +/− 19TCAGGCCCTGGGTACAATT 700 chr3 58141920 58141938 +/− 19CAGGCCCTGGGTACAATTT 701 chr3 58141921 58141939 +/− 19AGGCCCTGGGTACAATTTT 702 chr3 58141922 58141940 +/− 19GGCCCTGGGTACAATTTTG 703 chr3 58141923 58141941 +/− 19GCCCTGGGTACAATTTTGG 704 chr3 58141924 58141942 +/− 19CCCTGGGTACAATTTTGGT 705 chr3 58141925 58141943 +/− 19CCTGGGTACAATTTTGGTT 706 chr3 58141926 58141944 +/− 19CTGGGTACAATTTTGGTTT 707 chr3 58141927 58141945 +/− 19TGGGTACAATTTTGGTTTT 708 chr3 58141928 58141946 +/− 19GGGTACAATTTTGGTTTTT 709 chr3 58141929 58141947 +/− 19GGTACAATTTTGGTTTTTT 710 chr3 58141930 58141948 +/− 19GTACAATTTTGGTTTTTTC 711 chr3 58141931 58141949 +/− 19TACAATTTTGGTTTTTTCC 712 chr3 58141932 58141950 +/− 19ACAATTTTGGTTTTTTCCT 713 chr3 58141933 58141951 +/− 19CAATTTTGGTTTTTTCCTT 714 chr3 58141934 58141952 +/− 19AATTTTGGTTTTTTCCTTT 715 chr3 58141935 58141953 +/− 19ATTTTGGTTTTTTCCTTTT 716 chr3 58141936 58141954 +/− 19TTTTGGTTTTTTCCTTTTT 717 chr3 58141937 58141955 +/− 19TTTGGTTTTTTCCTTTTTG 718 chr3 58141938 58141956 +/− 19TTGGTTTTTTCCTTTTTGT 719 chr3 58141939 58141957 +/− 19TGGTTTTTTCCTTTTTGTG 720 chr3 58141940 58141958 +/− 19GGTTTTTTCCTTTTTGTGT 721 chr3 58141941 58141959 +/− 19GTTTTTTCCTTTTTGTGTT 722 chr3 58141942 58141960 +/− 19TTTTTTCCTTTTTGTGTTT 723 chr3 58141943 58141961 +/− 19TTTTTCCTTTTTGTGTTTC 724 chr3 58141944 58141962 +/− 19TTTTCCTTTTTGTGTTTCT 725 chr3 58141945 58141963 +/− 19TTTCCTTTTTGTGTTTCTG 726 chr3 58141946 58141964 +/− 19TTCCTTTTTGTGTTTCTGT 727 chr3 58141947 58141965 +/− 19TCCTTTTTGTGTTTCTGTG 728 chr3 58141948 58141966 +/− 19CCTTTTTGTGTTTCTGTGT 729 chr3 58141949 58141967 +/− 19CTTTTTGTGTTTCTGTGTT 730 chr3 58141950 58141968 +/− 19TTTTTGTGTTTCTGTGTTT 731 chr3 58141951 58141969 +/− 19TTTTGTGTTTCTGTGTTTA 732 chr3 58141952 58141970 +/− 19TTTGTGTTTCTGTGTTTAC 733 chr3 58141953 58141971 +/− 19TTGTGTTTCTGTGTTTACT 734 chr3 58141954 58141972 +/− 19TGTGTTTCTGTGTTTACTC 735 chr3 58141955 58141973 +/− 19GTGTTTCTGTGTTTACTCA 736 chr3 58141956 58141974 +/− 19TGTTTCTGTGTTTACTCAG 737 chr3 58141957 58141975 +/− 19GTTTCTGTGTTTACTCAGC 738 chr3 58141958 58141976 +/− 19TTTCTGTGTTTACTCAGCC 739 chr3 58141959 58141977 +/− 19TTCTGTGTTTACTCAGCCT 740 chr3 58141960 58141978 +/− 19TCTGTGTTTACTCAGCCTT 741 chr3 58141961 58141979 +/− 19CTGTGTTTACTCAGCCTTC 742 chr3 58141962 58141980 +/− 19TGTGTTTACTCAGCCTTCA 743 chr3 58141963 58141981 +/− 19GTGTTTACTCAGCCTTCAT 744 chr3 58141964 58141982 +/− 19TGTTTACTCAGCCTTCATT 745 chr3 58141965 58141983 +/− 19GTTTACTCAGCCTTCATTT 746 chr3 58141966 58141984 +/− 19TTTACTCAGCCTTCATTTC 747 chr3 58141967 58141985 +/− 19TTACTCAGCCTTCATTTCA 748 chr3 58141968 58141986 +/− 19TACTCAGCCTTCATTTCAG 749 chr3 58141969 58141987 +/− 19ACTCAGCCTTCATTTCAGA 750 chr3 58141970 58141988 +/− 19CTCAGCCTTCATTTCAGAA 751 chr3 58141971 58141989 +/− 19TCAGCCTTCATTTCAGAAA 752 chr3 58141972 58141990 +/− 19CAGCCTTCATTTCAGAAAA 753 chr3 58141973 58141991 +/− 19AGCCTTCATTTCAGAAAAT 754 chr3 58141974 58141992 +/− 19GCCTTCATTTCAGAAAATC 755 chr3 58141975 58141993 +/− 19CCTTCATTTCAGAAAATCT 756 chr3 58141976 58141994 +/− 19CTTCATTTCAGAAAATCTG 757 chr3 58141977 58141995 +/− 19TTCATTTCAGAAAATCTGC 758 chr3 58141978 58141996 +/− 19TCATTTCAGAAAATCTGCC 759 chr3 58141979 58141997 +/− 19CATTTCAGAAAATCTGCCA 760 chr3 58141980 58141998 +/− 19ATTTCAGAAAATCTGCCAT 761 chr3 58141981 58141999 +/− 19TTTCAGAAAATCTGCCATC 762 chr3 58141982 58142000 +/− 19TTCAGAAAATCTGCCATCT 763 chr3 58141983 58142001 +/− 19TCAGAAAATCTGCCATCTG 764 chr3 58141984 58142002 +/− 19CAGAAAATCTGCCATCTGC 765 chr3 58141985 58142003 +/− 19AGAAAATCTGCCATCTGCT 766 chr3 58141986 58142004 +/− 19GAAAATCTGCCATCTGCTT 767 chr3 58141987 58142005 +/− 19AAAATCTGCCATCTGCTTC 768 chr3 58141988 58142006 +/− 19AAATCTGCCATCTGCTTCT 769 chr3 58141989 58142007 +/− 19AATCTGCCATCTGCTTCTG 770 chr3 58141990 58142008 +/− 19ATCTGCCATCTGCTTCTGG 771 chr3 58141991 58142009 +/− 19TCTGCCATCTGCTTCTGGG 772 chr3 58141992 58142010 +/− 19CTGCCATCTGCTTCTGGGA 773 chr3 58141993 58142011 +/− 19TGCCATCTGCTTCTGGGAT 774 chr3 58141994 58142012 +/− 19GCCATCTGCTTCTGGGATT 775 chr3 58141995 58142013 +/− 19CCATCTGCTTCTGGGATTG 776 chr3 58141996 58142014 +/− 19CATCTGCTTCTGGGATTGC 777 chr3 58141997 58142015 +/− 19ATCTGCTTCTGGGATTGCT 778 chr3 58141998 58142016 +/− 19TCTGCTTCTGGGATTGCTT 779 chr3 58141999 58142017 +/− 19CTGCTTCTGGGATTGCTTA 780 chr3 58142000 58142018 +/− 19TGCTTCTGGGATTGCTTAA 781 chr3 58142001 58142019 +/− 19GCTTCTGGGATTGCTTAAG 782 chr3 58142002 58142020 +/− 19CTTCTGGGATTGCTTAAGC 783 chr3 58142003 58142021 +/− 19TTCTGGGATTGCTTAAGCC 784 chr3 58142004 58142022 +/− 19TCTGGGATTGCTTAAGCCC 785 chr3 58142005 58142023 +/− 19CTGGGATTGCTTAAGCCCT 786 chr3 58142006 58142024 +/− 19TGGGATTGCTTAAGCCCTG 787 chr3 58142007 58142025 +/− 19GGGATTGCTTAAGCCCTGT 788 chr3 58142008 58142026 +/− 19GGATTGCTTAAGCCCTGTG 789 chr3 58142009 58142027 +/− 19GATTGCTTAAGCCCTGTGG 790 chr3 58142010 58142028 +/− 19ATTGCTTAAGCCCTGTGGG 791 chr3 58142011 58142029 +/− 19TTGCTTAAGCCCTGTGGGT 792 chr3 58142012 58142030 +/− 19TGCTTAAGCCCTGTGGGTG 793 chr3 58142013 58142031 +/− 19GCTTAAGCCCTGTGGGTGT 794 chr3 58142014 58142032 +/− 19CTTAAGCCCTGTGGGTGTC 795 chr3 58142015 58142033 +/− 19TTAAGCCCTGTGGGTGTCC 796 chr3 58142016 58142034 +/− 19TAAGCCCTGTGGGTGTCCT 797 chr3 58142017 58142035 +/− 19AAGCCCTGTGGGTGTCCTG 798 chr3 58142018 58142036 +/− 19AGCCCTGTGGGTGTCCTGG 799 chr3 58142019 58142037 +/− 19GCCCTGTGGGTGTCCTGGT 800 chr3 58142020 58142038 +/− 19CCCTGTGGGTGTCCTGGTC 801 chr3 58142021 58142039 +/− 19CCTGTGGGTGTCCTGGTCA 802 chr3 58142022 58142040 +/− 19CTGTGGGTGTCCTGGTCAT 803 chr3 58142023 58142041 +/− 19TGTGGGTGTCCTGGTCATT 804 chr3 58142024 58142042 +/− 19GTGGGTGTCCTGGTCATTG 805 chr3 58142025 58142043 +/− 19TGGGTGTCCTGGTCATTGG 806 chr3 58142026 58142044 +/− 19GGGTGTCCTGGTCATTGGT 807

TABLE 6 20-mer target-specific ASOs SEQ ID CHR START END STRAND kmerSEQUENCE NO: chr3 58141828 58141847 +/− 20 CCCAACTAATCTCCATTTGC 808 chr358141829 58141848 +/− 20 CCAACTAATCTCCATTTGCC 809 chr3 58141830 58141849+/− 20 CAACTAATCTCCATTTGCCA 810 chr3 58141831 58141850 +/− 20AACTAATCTCCATTTGCCAC 811 chr3 58141832 58141851 +/− 20ACTAATCTCCATTTGCCACT 812 chr3 58141833 58141852 +/− 20CTAATCTCCATTTGCCACTG 813 chr3 58141834 58141853 +/− 20TAATCTCCATTTGCCACTGA 814 chr3 58141835 58141854 +/− 20AATCTCCATTTGCCACTGAC 815 chr3 58141836 58141855 +/− 20ATCTCCATTTGCCACTGACC 816 chr3 58141837 58141856 +/− 20TCTCCATTTGCCACTGACCA 817 chr3 58141838 58141857 +/− 20CTCCATTTGCCACTGACCAG 818 chr3 58141839 58141858 +/− 20TCCATTTGCCACTGACCAGG 819 chr3 58141840 58141859 +/− 20CCATTTGCCACTGACCAGGC 820 chr3 58141841 58141860 +/− 20CATTTGCCACTGACCAGGCC 821 chr3 58141842 58141861 +/− 20ATTTGCCACTGACCAGGCCA 822 chr3 58141843 58141862 +/− 20TTTGCCACTGACCAGGCCAC 823 chr3 58141844 58141863 +/− 20TTGCCACTGACCAGGCCACA 824 chr3 58141845 58141864 +/− 20TGCCACTGACCAGGCCACAG 825 chr3 58141846 58141865 +/− 20GCCACTGACCAGGCCACAGA 826 chr3 58141847 58141866 +/− 20CCACTGACCAGGCCACAGAT 827 chr3 58141848 58141867 +/− 20CACTGACCAGGCCACAGATG 828 chr3 58141849 58141868 +/− 20ACTGACCAGGCCACAGATGG 829 chr3 58141850 58141869 +/− 20CTGACCAGGCCACAGATGGG 830 chr3 58141851 58141870 +/− 20TGACCAGGCCACAGATGGGG 831 chr3 58141852 58141871 +/− 20GACCAGGCCACAGATGGGGA 832 chr3 58141853 58141872 +/− 20ACCAGGCCACAGATGGGGAA 833 chr3 58141854 58141873 +/− 20CCAGGCCACAGATGGGGAAG 834 chr3 58141855 58141874 +/− 20CAGGCCACAGATGGGGAAGT 835 chr3 58141856 58141875 +/− 20AGGCCACAGATGGGGAAGTC 836 chr3 58141857 58141876 +/− 20GGCCACAGATGGGGAAGTCA 837 chr3 58141858 58141877 +/− 20GCCACAGATGGGGAAGTCAC 838 chr3 58141859 58141878 +/− 20CCACAGATGGGGAAGTCACA 839 chr3 58141860 58141879 +/− 20CACAGATGGGGAAGTCACAG 840 chr3 58141861 58141880 +/− 20ACAGATGGGGAAGTCACAGC 841 chr3 58141862 58141881 +/− 20CAGATGGGGAAGTCACAGCC 842 chr3 58141863 58141882 +/− 20AGATGGGGAAGTCACAGCCG 843 chr3 58141864 58141883 +/− 20GATGGGGAAGTCACAGCCGT 844 chr3 58141865 58141884 +/− 20ATGGGGAAGTCACAGCCGTG 845 chr3 58141866 58141885 +/− 20TGGGGAAGTCACAGCCGTGG 846 chr3 58141867 58141886 +/− 20GGGGAAGTCACAGCCGTGGA 847 chr3 58141868 58141887 +/− 20GGGAAGTCACAGCCGTGGAG 848 chr3 58141869 58141888 +/− 20GGAAGTCACAGCCGTGGAGG 849 chr3 58141870 58141889 +/− 20GAAGTCACAGCCGTGGAGGA 850 chr3 58141871 58141890 +/− 20AAGTCACAGCCGTGGAGGAG 851 chr3 58141872 58141891 +/− 20AGTCACAGCCGTGGAGGAGG 852 chr3 58141873 58141892 +/− 20GTCACAGCCGTGGAGGAGGC 853 chr3 58141874 58141893 +/− 20TCACAGCCGTGGAGGAGGCA 854 chr3 58141875 58141894 +/− 20CACAGCCGTGGAGGAGGCAC 855 chr3 58141876 58141895 +/− 20ACAGCCGTGGAGGAGGCACC 856 chr3 58141877 58141896 +/− 20CAGCCGTGGAGGAGGCACCG 857 chr3 58141878 58141897 +/− 20AGCCGTGGAGGAGGCACCGG 858 chr3 58141879 58141898 +/− 20GCCGTGGAGGAGGCACCGGT 859 chr3 58141880 58141899 +/− 20CCGTGGAGGAGGCACCGGTA 860 chr3 58141881 58141900 +/− 20CGTGGAGGAGGCACCGGTAA 861 chr3 58141882 58141901 +/− 20GTGGAGGAGGCACCGGTAAA 862 chr3 58141883 58141902 +/− 20TGGAGGAGGCACCGGTAAAT 863 chr3 58141884 58141903 +/− 20GGAGGAGGCACCGGTAAATG 864 chr3 58141885 58141904 +/− 20GAGGAGGCACCGGTAAATGC 865 chr3 58141886 58141905 +/− 20AGGAGGCACCGGTAAATGCA 866 chr3 58141887 58141906 +/− 20GGAGGCACCGGTAAATGCAT 867 chr3 58141888 58141907 +/− 20GAGGCACCGGTAAATGCATG 868 chr3 58141889 58141908 +/− 20AGGCACCGGTAAATGCATGT 869 chr3 58141890 58141909 +/− 20GGCACCGGTAAATGCATGTC 870 chr3 58141891 58141910 +/− 20GCACCGGTAAATGCATGTCC 871 chr3 58141892 58141911 +/− 20CACCGGTAAATGCATGTCCC 872 chr3 58141893 58141912 +/− 20ACCGGTAAATGCATGTCCCC 873 chr3 58141894 58141913 +/− 20CCGGTAAATGCATGTCCCCC 874 chr3 58141895 58141914 +/− 20CGGTAAATGCATGTCCCCCT 875 chr3 58141896 58141915 +/− 20GGTAAATGCATGTCCCCCTG 876 chr3 58141897 58141916 +/− 20GTAAATGCATGTCCCCCTGG 877 chr3 58141898 58141917 +/− 20TAAATGCATGTCCCCCTGGA 878 chr3 58141899 58141918 +/− 20AAATGCATGTCCCCCTGGAT 879 chr3 58141900 58141919 +/− 20AATGCATGTCCCCCTGGATT 880 chr3 58141901 58141920 +/− 20ATGCATGTCCCCCTGGATTC 881 chr3 58141902 58141921 +/− 20TGCATGTCCCCCTGGATTCA 882 chr3 58141903 58141922 +/− 20GCATGTCCCCCTGGATTCAG 883 chr3 58141904 58141923 +/− 20CATGTCCCCCTGGATTCAGG 884 chr3 58141905 58141924 +/− 20ATGTCCCCCTGGATTCAGGC 885 chr3 58141906 58141925 +/− 20TGTCCCCCTGGATTCAGGCC 886 chr3 58141907 58141926 +/− 20GTCCCCCTGGATTCAGGCCC 887 chr3 58141908 58141927 +/− 20TCCCCCTGGATTCAGGCCCT 888 chr3 58141909 58141928 +/− 20CCCCCTGGATTCAGGCCCTG 889 chr3 58141910 58141929 +/− 20CCCCTGGATTCAGGCCCTGG 890 chr3 58141911 58141930 +/− 20CCCTGGATTCAGGCCCTGGG 891 chr3 58141912 58141931 +/− 20CCTGGATTCAGGCCCTGGGT 892 chr3 58141913 58141932 +/− 20CTGGATTCAGGCCCTGGGTA 893 chr3 58141914 58141933 +/− 20TGGATTCAGGCCCTGGGTAC 894 chr3 58141915 58141934 +/− 20GGATTCAGGCCCTGGGTACA 895 chr3 58141916 58141935 +/− 20GATTCAGGCCCTGGGTACAA 896 chr3 58141917 58141936 +/− 20ATTCAGGCCCTGGGTACAAT 897 chr3 58141918 58141937 +/− 20TTCAGGCCCTGGGTACAATT 898 chr3 58141919 58141938 +/− 20TCAGGCCCTGGGTACAATTT 899 chr3 58141920 58141939 +/− 20CAGGCCCTGGGTACAATTTT 900 chr3 58141921 58141940 +/− 20AGGCCCTGGGTACAATTTTG 901 chr3 58141922 58141941 +/− 20GGCCCTGGGTACAATTTTGG 902 chr3 58141923 58141942 +/− 20GCCCTGGGTACAATTTTGGT 903 chr3 58141924 58141943 +/− 20CCCTGGGTACAATTTTGGTT 904 chr3 58141925 58141944 +/− 20CCTGGGTACAATTTTGGTTT 905 chr3 58141926 58141945 +/− 20CTGGGTACAATTTTGGTTTT 906 chr3 58141927 58141946 +/− 20TGGGTACAATTTTGGTTTTT 907 chr3 58141928 58141947 +/− 20GGGTACAATTTTGGTTTTTT 908 chr3 58141929 58141948 +/− 20GGTACAATTTTGGTTTTTTC 909 chr3 58141930 58141949 +/− 20GTACAATTTTGGTTTTTTCC 910 chr3 58141931 58141950 +/− 20TACAATTTTGGTTTTTTCCT 911 chr3 58141932 58141951 +/− 20ACAATTTTGGTTTTTTCCTT 912 chr3 58141933 58141952 +/− 20CAATTTTGGTTTTTTCCTTT 913 chr3 58141934 58141953 +/− 20AATTTTGGTTTTTTCCTTTT 914 chr3 58141935 58141954 +/− 20ATTTTGGTTTTTTCCTTTTT 915 chr3 58141936 58141955 +/− 20TTTTGGTTTTTTCCTTTTTG 916 chr3 58141937 58141956 +/− 20TTTGGTTTTTTCCTTTTTGT 917 chr3 58141938 58141957 +/− 20TTGGTTTTTTCCTTTTTGTG 918 chr3 58141939 58141958 +/− 20TGGTTTTTTCCTTTTTGTGT 919 chr3 58141940 58141959 +/− 20GGTTTTTTCCTTTTTGTGTT 920 chr3 58141941 58141960 +/− 20GTTTTTTCCTTTTTGTGTTT 921 chr3 58141942 58141961 +/− 20TTTTTTCCTTTTTGTGTTTC 922 chr3 58141943 58141962 +/− 20TTTTTCCTTTTTGTGTTTCT 923 chr3 58141944 58141963 +/− 20TTTTCCTTTTTGTGTTTCTG 924 chr3 58141945 58141964 +/− 20TTTCCTTTTTGTGTTTCTGT 925 chr3 58141946 58141965 +/− 20TTCCTTTTTGTGTTTCTGTG 926 chr3 58141947 58141966 +/− 20TCCTTTTTGTGTTTCTGTGT 927 chr3 58141948 58141967 +/− 20CCTTTTTGTGTTTCTGTGTT 928 chr3 58141949 58141968 +/− 20CTTTTTGTGTTTCTGTGTTT 929 chr3 58141950 58141969 +/− 20TTTTTGTGTTTCTGTGTTTA 930 chr3 58141951 58141970 +/− 20TTTTGTGTTTCTGTGTTTAC 931 chr3 58141952 58141971 +/− 20TTTGTGTTTCTGTGTTTACT 932 chr3 58141953 58141972 +/− 20TTGTGTTTCTGTGTTTACTC 933 chr3 58141954 58141973 +/− 20TGTGTTTCTGTGTTTACTCA 934 chr3 58141955 58141974 +/− 20GTGTTTCTGTGTTTACTCAG 935 chr3 58141956 58141975 +/− 20TGTTTCTGTGTTTACTCAGC 936 chr3 58141957 58141976 +/− 20GTTTCTGTGTTTACTCAGCC 937 chr3 58141958 58141977 +/− 20TTTCTGTGTTTACTCAGCCT 938 chr3 58141959 58141978 +/− 20TTCTGTGTTTACTCAGCCTT 939 chr3 58141960 58141979 +/− 20TCTGTGTTTACTCAGCCTTC 940 chr3 58141961 58141980 +/− 20CTGTGTTTACTCAGCCTTCA 941 chr3 58141962 58141981 +/− 20TGTGTTTACTCAGCCTTCAT 942 chr3 58141963 58141982 +/− 20GTGTTTACTCAGCCTTCATT 943 chr3 58141964 58141983 +/− 20TGTTTACTCAGCCTTCATTT 944 chr3 58141965 58141984 +/− 20GTTTACTCAGCCTTCATTTC 945 chr3 58141966 58141985 +/− 20TTTACTCAGCCTTCATTTCA 946 chr3 58141967 58141986 +/− 20TTACTCAGCCTTCATTTCAG 947 chr3 58141968 58141987 +/− 20TACTCAGCCTTCATTTCAGA 948 chr3 58141969 58141988 +/− 20ACTCAGCCTTCATTTCAGAA 949 chr3 58141970 58141989 +/− 20CTCAGCCTTCATTTCAGAAA 950 chr3 58141971 58141990 +/− 20TCAGCCTTCATTTCAGAAAA 951 chr3 58141972 58141991 +/− 20CAGCCTTCATTTCAGAAAAT 952 chr3 58141973 58141992 +/− 20AGCCTTCATTTCAGAAAATC 953 chr3 58141974 58141993 +/− 20GCCTTCATTTCAGAAAATCT 954 chr3 58141975 58141994 +/− 20CCTTCATTTCAGAAAATCTG 955 chr3 58141976 58141995 +/− 20CTTCATTTCAGAAAATCTGC 956 chr3 58141977 58141996 +/− 20TTCATTTCAGAAAATCTGCC 957 chr3 58141978 58141997 +/− 20TCATTTCAGAAAATCTGCCA 958 chr3 58141979 58141998 +/− 20CATTTCAGAAAATCTGCCAT 959 chr3 58141980 58141999 +/− 20ATTTCAGAAAATCTGCCATC 960 chr3 58141981 58142000 +/− 20TTTCAGAAAATCTGCCATCT 961 chr3 58141982 58142001 +/− 20TTCAGAAAATCTGCCATCTG 962 chr3 58141983 58142002 +/− 20TCAGAAAATCTGCCATCTGC 963 chr3 58141984 58142003 +/− 20CAGAAAATCTGCCATCTGCT 964 chr3 58141985 58142004 +/− 20AGAAAATCTGCCATCTGCTT 965 chr3 58141986 58142005 +/− 20GAAAATCTGCCATCTGCTTC 966 chr3 58141987 58142006 +/− 20AAAATCTGCCATCTGCTTCT 967 chr3 58141988 58142007 +/− 20AAATCTGCCATCTGCTTCTG 968 chr3 58141989 58142008 +/− 20AATCTGCCATCTGCTTCTGG 969 chr3 58141990 58142009 +/− 20ATCTGCCATCTGCTTCTGGG 970 chr3 58141991 58142010 +/− 20TCTGCCATCTGCTTCTGGGA 971 chr3 58141992 58142011 +/− 20CTGCCATCTGCTTCTGGGAT 972 chr3 58141993 58142012 +/− 20TGCCATCTGCTTCTGGGATT 973 chr3 58141994 58142013 +/− 20GCCATCTGCTTCTGGGATTG 974 chr3 58141995 58142014 +/− 20CCATCTGCTTCTGGGATTGC 975 chr3 58141996 58142015 +/− 20CATCTGCTTCTGGGATTGCT 976 chr3 58141997 58142016 +/− 20ATCTGCTTCTGGGATTGCTT 977 chr3 58141998 58142017 +/− 20TCTGCTTCTGGGATTGCTTA 978 chr3 58141999 58142018 +/− 20CTGCTTCTGGGATTGCTTAA 979 chr3 58142000 58142019 +/− 20TGCTTCTGGGATTGCTTAAG 980 chr3 58142001 58142020 +/− 20GCTTCTGGGATTGCTTAAGC 981 chr3 58142002 58142021 +/− 20CTTCTGGGATTGCTTAAGCC 982 chr3 58142003 58142022 +/− 20TTCTGGGATTGCTTAAGCCC 983 chr3 58142004 58142023 +/− 20TCTGGGATTGCTTAAGCCCT 984 chr3 58142005 58142024 +/− 20CTGGGATTGCTTAAGCCCTG 985 chr3 58142006 58142025 +/− 20TGGGATTGCTTAAGCCCTGT 986 chr3 58142007 58142026 +/− 20GGGATTGCTTAAGCCCTGTG 987 chr3 58142008 58142027 +/− 20GGATTGCTTAAGCCCTGTGG 988 chr3 58142009 58142028 +/− 20GATTGCTTAAGCCCTGTGGG 989 chr3 58142010 58142029 +/− 20ATTGCTTAAGCCCTGTGGGT 990 chr3 58142011 58142030 +/− 20TTGCTTAAGCCCTGTGGGTG 991 chr3 58142012 58142031 +/− 20TGCTTAAGCCCTGTGGGTGT 992 chr3 58142013 58142032 +/− 20GCTTAAGCCCTGTGGGTGTC 993 chr3 58142014 58142033 +/− 20CTTAAGCCCTGTGGGTGTCC 994 chr3 58142015 58142034 +/− 20TTAAGCCCTGTGGGTGTCCT 995 chr3 58142016 58142035 +/− 20TAAGCCCTGTGGGTGTCCTG 996 chr3 58142017 58142036 +/− 20AAGCCCTGTGGGTGTCCTGG 997 chr3 58142018 58142037 +/− 20AGCCCTGTGGGTGTCCTGGT 998 chr3 58142019 58142038 +/− 20GCCCTGTGGGTGTCCTGGTC 999 chr3 58142020 58142039 +/− 20CCCTGTGGGTGTCCTGGTCA 1000 chr3 58142021 58142040 +/− 20CCTGTGGGTGTCCTGGTCAT 1001 chr3 58142022 58142041 +/− 20CTGTGGGTGTCCTGGTCATT 1002 chr3 58142023 58142042 +/− 20TGTGGGTGTCCTGGTCATTG 1003 chr3 58142024 58142043 +/− 20GTGGGTGTCCTGGTCATTGG 1004 chr3 58142025 58142044 +/− 20TGGGTGTCCTGGTCATTGGT 1005

TABLE 7 21-mer target-specific ASOs SEQ ID CHR START END STRAND kmerSEQUENCE NO: chr3 58141828 58141848 +/− 21 CCCAACTAATCTCCATTTGCC 1006chr3 58141829 58141849 +/− 21 CCAACTAATCTCCATTTGCCA 1007 chr3 5814183058141850 +/− 21 CAACTAATCTCCATTTGCCAC 1008 chr3 58141831 58141851 +/− 21AACTAATCTCCATTTGCCACT 1009 chr3 58141832 58141852 +/− 21ACTAATCTCCATTTGCCACTG 1010 chr3 58141833 58141853 +/− 21CTAATCTCCATTTGCCACTGA 1011 chr3 58141834 58141854 +/− 21TAATCTCCATTTGCCACTGAC 1012 chr3 58141835 58141855 +/− 21AATCTCCATTTGCCACTGACC 1013 chr3 58141836 58141856 +/− 21ATCTCCATTTGCCACTGACCA 1014 chr3 58141837 58141857 +/− 21TCTCCATTTGCCACTGACCAG 1015 chr3 58141838 58141858 +/− 21CTCCATTTGCCACTGACCAGG 1016 chr3 58141839 58141859 +/− 21TCCATTTGCCACTGACCAGGC 1017 chr3 58141840 58141860 +/− 21CCATTTGCCACTGACCAGGCC 1018 chr3 58141841 58141861 +/− 21CATTTGCCACTGACCAGGCCA 1019 chr3 58141842 58141862 +/− 21ATTTGCCACTGACCAGGCCAC 1020 chr3 58141843 58141863 +/− 21TTTGCCACTGACCAGGCCACA 1021 chr3 58141844 58141864 +/− 21TTGCCACTGACCAGGCCACAG 1022 chr3 58141845 58141865 +/− 21TGCCACTGACCAGGCCACAGA 1023 chr3 58141846 58141866 +/− 21GCCACTGACCAGGCCACAGAT 1024 chr3 58141847 58141867 +/− 21CCACTGACCAGGCCACAGATG 1025 chr3 58141848 58141868 +/− 21CACTGACCAGGCCACAGATGG 1026 chr3 58141849 58141869 +/− 21ACTGACCAGGCCACAGATGGG 1027 chr3 58141850 58141870 +/− 21CTGACCAGGCCACAGATGGGG 1028 chr3 58141851 58141871 +/− 21TGACCAGGCCACAGATGGGGA 1029 chr3 58141852 58141872 +/− 21GACCAGGCCACAGATGGGGAA 1030 chr3 58141853 58141873 +/− 21ACCAGGCCACAGATGGGGAAG 1031 chr3 58141854 58141874 +/− 21CCAGGCCACAGATGGGGAAGT 1032 chr3 58141855 58141875 +/− 21CAGGCCACAGATGGGGAAGTC 1033 chr3 58141856 58141876 +/− 21AGGCCACAGATGGGGAAGTCA 1034 chr3 58141857 58141877 +/− 21GGCCACAGATGGGGAAGTCAC 1035 chr3 58141858 58141878 +/− 21GCCACAGATGGGGAAGTCACA 1036 chr3 58141859 58141879 +/− 21CCACAGATGGGGAAGTCACAG 1037 chr3 58141860 58141880 +/− 21CACAGATGGGGAAGTCACAGC 1038 chr3 58141861 58141881 +/− 21ACAGATGGGGAAGTCACAGCC 1039 chr3 58141862 58141882 +/− 21CAGATGGGGAAGTCACAGCCG 1040 chr3 58141863 58141883 +/− 21AGATGGGGAAGTCACAGCCGT 1041 chr3 58141864 58141884 +/− 21GATGGGGAAGTCACAGCCGTG 1042 chr3 58141865 58141885 +/− 21ATGGGGAAGTCACAGCCGTGG 1043 chr3 58141866 58141886 +/− 21TGGGGAAGTCACAGCCGTGGA 1044 chr3 58141867 58141887 +/− 21GGGGAAGTCACAGCCGTGGAG 1045 chr3 58141868 58141888 +/− 21GGGAAGTCACAGCCGTGGAGG 1046 chr3 58141869 58141889 +/− 21GGAAGTCACAGCCGTGGAGGA 1047 chr3 58141870 58141890 +/− 21GAAGTCACAGCCGTGGAGGAG 1048 chr3 58141871 58141891 +/− 21AAGTCACAGCCGTGGAGGAGG 1049 chr3 58141872 58141892 +/− 21AGTCACAGCCGTGGAGGAGGC 1050 chr3 58141873 58141893 +/− 21GTCACAGCCGTGGAGGAGGCA 1051 chr3 58141874 58141894 +/− 21TCACAGCCGTGGAGGAGGCAC 1052 chr3 58141875 58141895 +/− 21CACAGCCGTGGAGGAGGCACC 1053 chr3 58141876 58141896 +/− 21ACAGCCGTGGAGGAGGCACCG 1054 chr3 58141877 58141897 +/− 21CAGCCGTGGAGGAGGCACCGG 1055 chr3 58141878 58141898 +/− 21AGCCGTGGAGGAGGCACCGGT 1056 chr3 58141879 58141899 +/− 21GCCGTGGAGGAGGCACCGGTA 1057 chr3 58141880 58141900 +/− 21CCGTGGAGGAGGCACCGGTAA 1058 chr3 58141881 58141901 +/− 21CGTGGAGGAGGCACCGGTAAA 1059 chr3 58141882 58141902 +/− 21GTGGAGGAGGCACCGGTAAAT 1060 chr3 58141883 58141903 +/− 21TGGAGGAGGCACCGGTAAATG 1061 chr3 58141884 58141904 +/− 21GGAGGAGGCACCGGTAAATGC 1062 chr3 58141885 58141905 +/− 21GAGGAGGCACCGGTAAATGCA 1063 chr3 58141886 58141906 +/− 21AGGAGGCACCGGTAAATGCAT 1064 chr3 58141887 58141907 +/− 21GGAGGCACCGGTAAATGCATG 1065 chr3 58141888 58141908 +/− 21GAGGCACCGGTAAATGCATGT 1066 chr3 58141889 58141909 +/− 21AGGCACCGGTAAATGCATGTC 1067 chr3 58141890 58141910 +/− 21GGCACCGGTAAATGCATGTCC 1068 chr3 58141891 58141911 +/− 21GCACCGGTAAATGCATGTCCC 1069 chr3 58141892 58141912 +/− 21CACCGGTAAATGCATGTCCCC 1070 chr3 58141893 58141913 +/− 21ACCGGTAAATGCATGTCCCCC 1071 chr3 58141894 58141914 +/− 21CCGGTAAATGCATGTCCCCCT 1072 chr3 58141895 58141915 +/− 21CGGTAAATGCATGTCCCCCTG 1073 chr3 58141896 58141916 +/− 21GGTAAATGCATGTCCCCCTGG 1074 chr3 58141897 58141917 +/− 21GTAAATGCATGTCCCCCTGGA 1075 chr3 58141898 58141918 +/− 21TAAATGCATGTCCCCCTGGAT 1076 chr3 58141899 58141919 +/− 21AAATGCATGTCCCCCTGGATT 1077 chr3 58141900 58141920 +/− 21AATGCATGTCCCCCTGGATTC 1078 chr3 58141901 58141921 +/− 21ATGCATGTCCCCCTGGATTCA 1079 chr3 58141902 58141922 +/− 21TGCATGTCCCCCTGGATTCAG 1080 chr3 58141903 58141923 +/− 21GCATGTCCCCCTGGATTCAGG 1081 chr3 58141904 58141924 +/− 21CATGTCCCCCTGGATTCAGGC 1082 chr3 58141905 58141925 +/− 21ATGTCCCCCTGGATTCAGGCC 1083 chr3 58141906 58141926 +/− 21TGTCCCCCTGGATTCAGGCCC 1084 chr3 58141907 58141927 +/− 21GTCCCCCTGGATTCAGGCCCT 1085 chr3 58141908 58141928 +/− 21TCCCCCTGGATTCAGGCCCTG 1086 chr3 58141909 58141929 +/− 21CCCCCTGGATTCAGGCCCTGG 1087 chr3 58141910 58141930 +/− 21CCCCTGGATTCAGGCCCTGGG 1088 chr3 58141911 58141931 +/− 21CCCTGGATTCAGGCCCTGGGT 1089 chr3 58141912 58141932 +/− 21CCTGGATTCAGGCCCTGGGTA 1090 chr3 58141913 58141933 +/− 21CTGGATTCAGGCCCTGGGTAC 1091 chr3 58141914 58141934 +/− 21TGGATTCAGGCCCTGGGTACA 1092 chr3 58141915 58141935 +/− 21GGATTCAGGCCCTGGGTACAA 1093 chr3 58141916 58141936 +/− 21GATTCAGGCCCTGGGTACAAT 1094 chr3 58141917 58141937 +/− 21ATTCAGGCCCTGGGTACAATT 1095 chr3 58141918 58141938 +/− 21TTCAGGCCCTGGGTACAATTT 1096 chr3 58141919 58141939 +/− 21TCAGGCCCTGGGTACAATTTT 1097 chr3 58141920 58141940 +/− 21CAGGCCCTGGGTACAATTTTG 1098 chr3 58141921 58141941 +/− 21AGGCCCTGGGTACAATTTTGG 1099 chr3 58141922 58141942 +/− 21GGCCCTGGGTACAATTTTGGT 1100 chr3 58141923 58141943 +/− 21GCCCTGGGTACAATTTTGGTT 1101 chr3 58141924 58141944 +/− 21CCCTGGGTACAATTTTGGTTT 1102 chr3 58141925 58141945 +/− 21CCTGGGTACAATTTTGGTTTT 1103 chr3 58141926 58141946 +/− 21CTGGGTACAATTTTGGTTTTT 1104 chr3 58141927 58141947 +/− 21TGGGTACAATTTTGGTTTTTT 1105 chr3 58141928 58141948 +/− 21GGGTACAATTTTGGTTTTTTC 1106 chr3 58141929 58141949 +/− 21GGTACAATTTTGGTTTTTTCC 1107 chr3 58141930 58141950 +/− 21GTACAATTTTGGTTTTTTCCT 1108 chr3 58141931 58141951 +/− 21TACAATTTTGGTTTTTTCCTT 1109 chr3 58141932 58141952 +/− 21ACAATTTTGGTTTTTTCCTTT 1110 chr3 58141933 58141953 +/− 21CAATTTTGGTTTTTTCCTTTT 1111 chr3 58141934 58141954 +/− 21AATTTTGGTTTTTTCCTTTTT 1112 chr3 58141935 58141955 +/− 21ATTTTGGTTTTTTCCTTTTTG 1113 chr3 58141936 58141956 +/− 21TTTTGGTTTTTTCCTTTTTGT 1114 chr3 58141937 58141957 +/− 21TTTGGTTTTTTCCTTTTTGTG 1115 chr3 58141938 58141958 +/− 21TTGGTTTTTTCCTTTTTGTGT 1116 chr3 58141939 58141959 +/− 21TGGTTTTTTCCTTTTTGTGTT 1117 chr3 58141940 58141960 +/− 21GGTTTTTTCCTTTTTGTGTTT 1118 chr3 58141941 58141961 +/− 21GTTTTTTCCTTTTTGTGTTTC 1119 chr3 58141942 58141962 +/− 21TTTTTTCCTTTTTGTGTTTCT 1120 chr3 58141943 58141963 +/− 21TTTTTCCTTTTTGTGTTTCTG 1121 chr3 58141944 58141964 +/− 21TTTTCCTTTTTGTGTTTCTGT 1122 chr3 58141945 58141965 +/− 21TTTCCTTTTTGTGTTTCTGTG 1123 chr3 58141946 58141966 +/− 21TTCCTTTTTGTGTTTCTGTGT 1124 chr3 58141947 58141967 +/− 21TCCTTTTTGTGTTTCTGTGTT 1125 chr3 58141948 58141968 +/− 21CCTTTTTGTGTTTCTGTGTTT 1126 chr3 58141949 58141969 +/− 21CTTTTTGTGTTTCTGTGTTTA 1127 chr3 58141950 58141970 +/− 21TTTTTGTGTTTCTGTGTTTAC 1128 chr3 58141951 58141971 +/− 21TTTTGTGTTTCTGTGTTTACT 1129 chr3 58141952 58141972 +/− 21TTTGTGTTTCTGTGTTTACTC 1130 chr3 58141953 58141973 +/− 21TTGTGTTTCTGTGTTTACTCA 1131 chr3 58141954 58141974 +/− 21TGTGTTTCTGTGTTTACTCAG 1132 chr3 58141955 58141975 +/− 21GTGTTTCTGTGTTTACTCAGC 1133 chr3 58141956 58141976 +/− 21TGTTTCTGTGTTTACTCAGCC 1134 chr3 58141957 58141977 +/− 21GTTTCTGTGTTTACTCAGCCT 1135 chr3 58141958 58141978 +/− 21TTTCTGTGTTTACTCAGCCTT 1136 chr3 58141959 58141979 +/− 21TTCTGTGTTTACTCAGCCTTC 1137 chr3 58141960 58141980 +/− 21TCTGTGTTTACTCAGCCTTCA 1138 chr3 58141961 58141981 +/− 21CTGTGTTTACTCAGCCTTCAT 1139 chr3 58141962 58141982 +/− 21TGTGTTTACTCAGCCTTCATT 1140 chr3 58141963 58141983 +/− 21GTGTTTACTCAGCCTTCATTT 1141 chr3 58141964 58141984 +/− 21TGTTTACTCAGCCTTCATTTC 1142 chr3 58141965 58141985 +/− 21GTTTACTCAGCCTTCATTTCA 1143 chr3 58141966 58141986 +/− 21TTTACTCAGCCTTCATTTCAG 1144 chr3 58141967 58141987 +/− 21TTACTCAGCCTTCATTTCAGA 1145 chr3 58141968 58141988 +/− 21TACTCAGCCTTCATTTCAGAA 1146 chr3 58141969 58141989 +/− 21ACTCAGCCTTCATTTCAGAAA 1147 chr3 58141970 58141990 +/− 21CTCAGCCTTCATTTCAGAAAA 1148 chr3 58141971 58141991 +/− 21TCAGCCTTCATTTCAGAAAAT 1149 chr3 58141972 58141992 +/− 21CAGCCTTCATTTCAGAAAATC 1150 chr3 58141973 58141993 +/− 21AGCCTTCATTTCAGAAAATCT 1151 chr3 58141974 58141994 +/− 21GCCTTCATTTCAGAAAATCTG 1152 chr3 58141975 58141995 +/− 21CCTTCATTTCAGAAAATCTGC 1153 chr3 58141976 58141996 +/− 21CTTCATTTCAGAAAATCTGCC 1154 chr3 58141977 58141997 +/− 21TTCATTTCAGAAAATCTGCCA 1155 chr3 58141978 58141998 +/− 21TCATTTCAGAAAATCTGCCAT 1156 chr3 58141979 58141999 +/− 21CATTTCAGAAAATCTGCCATC 1157 chr3 58141980 58142000 +/− 21ATTTCAGAAAATCTGCCATCT 1158 chr3 58141981 58142001 +/− 21TTTCAGAAAATCTGCCATCTG 1159 chr3 58141982 58142002 +/− 21TTCAGAAAATCTGCCATCTGC 1160 chr3 58141983 58142003 +/− 21TCAGAAAATCTGCCATCTGCT 1161 chr3 58141984 58142004 +/− 21CAGAAAATCTGCCATCTGCTT 1162 chr3 58141985 58142005 +/− 21AGAAAATCTGCCATCTGCTTC 1163 chr3 58141986 58142006 +/− 21GAAAATCTGCCATCTGCTTCT 1164 chr3 58141987 58142007 +/− 21AAAATCTGCCATCTGCTTCTG 1165 chr3 58141988 58142008 +/− 21AAATCTGCCATCTGCTTCTGG 1166 chr3 58141989 58142009 +/− 21AATCTGCCATCTGCTTCTGGG 1167 chr3 58141990 58142010 +/− 21ATCTGCCATCTGCTTCTGGGA 1168 chr3 58141991 58142011 +/− 21TCTGCCATCTGCTTCTGGGAT 1169 chr3 58141992 58142012 +/− 21CTGCCATCTGCTTCTGGGATT 1170 chr3 58141993 58142013 +/− 21TGCCATCTGCTTCTGGGATTG 1171 chr3 58141994 58142014 +/− 21GCCATCTGCTTCTGGGATTGC 1172 chr3 58141995 58142015 +/− 21CCATCTGCTTCTGGGATTGCT 1173 chr3 58141996 58142016 +/− 21CATCTGCTTCTGGGATTGCTT 1174 chr3 58141997 58142017 +/− 21ATCTGCTTCTGGGATTGCTTA 1175 chr3 58141998 58142018 +/− 21TCTGCTTCTGGGATTGCTTAA 1176 chr3 58141999 58142019 +/− 21CTGCTTCTGGGATTGCTTAAG 1177 chr3 58142000 58142020 +/− 21TGCTTCTGGGATTGCTTAAGC 1178 chr3 58142001 58142021 +/− 21GCTTCTGGGATTGCTTAAGCC 1179 chr3 58142002 58142022 +/− 21CTTCTGGGATTGCTTAAGCCC 1180 chr3 58142003 58142023 +/− 21TTCTGGGATTGCTTAAGCCCT 1181 chr3 58142004 58142024 +/− 21TCTGGGATTGCTTAAGCCCTG 1182 chr3 58142005 58142025 +/− 21CTGGGATTGCTTAAGCCCTGT 1183 chr3 58142006 58142026 +/− 21TGGGATTGCTTAAGCCCTGTG 1184 chr3 58142007 58142027 +/− 21GGGATTGCTTAAGCCCTGTGG 1185 chr3 58142008 58142028 +/− 21GGATTGCTTAAGCCCTGTGGG 1186 chr3 58142009 58142029 +/− 21GATTGCTTAAGCCCTGTGGGT 1187 chr3 58142010 58142030 +/− 21ATTGCTTAAGCCCTGTGGGTG 1188 chr3 58142011 58142031 +/− 21TTGCTTAAGCCCTGTGGGTGT 1189 chr3 58142012 58142032 +/− 21TGCTTAAGCCCTGTGGGTGTC 1190 chr3 58142013 58142033 +/− 21GCTTAAGCCCTGTGGGTGTCC 1191 chr3 58142014 58142034 +/− 21CTTAAGCCCTGTGGGTGTCCT 1192 chr3 58142015 58142035 +/− 21TTAAGCCCTGTGGGTGTCCTG 1193 chr3 58142016 58142036 +/− 21TAAGCCCTGTGGGTGTCCTGG 1194 chr3 58142017 58142037 +/− 21AAGCCCTGTGGGTGTCCTGGT 1195 chr3 58142018 58142038 +/− 21AGCCCTGTGGGTGTCCTGGTC 1196 chr3 58142019 58142039 +/− 21GCCCTGTGGGTGTCCTGGTCA 1197 chr3 58142020 58142040 +/− 21CCCTGTGGGTGTCCTGGTCAT 1198 chr3 58142021 58142041 +/− 21CCTGTGGGTGTCCTGGTCATT 1199 chr3 58142022 58142042 +/− 21CTGTGGGTGTCCTGGTCATTG 1200 chr3 58142023 58142043 +/− 21TGTGGGTGTCCTGGTCATTGG 1201 chr3 58142024 58142044 +/− 21GTGGGTGTCCTGGTCATTGGT 1202

TABLE 8 22-mer target-specific ASOs SEQ ID CHR START END STRAND kmerSEQUENCE NO: chr3 58141828 58141849 +/− 22 CCCAACTAATCTCCATTTGCCA 1203chr3 58141829 58141850 +/− 22 CCAACTAATCTCCATTTGCCAC 1204 chr3 5814183058141851 +/− 22 CAACTAATCTCCATTTGCCACT 1205 chr3 58141831 58141852 +/−22 AACTAATCTCCATTTGCCACTG 1206 chr3 58141832 58141853 +/− 22ACTAATCTCCATTTGCCACTGA 1207 chr3 58141833 58141854 +/− 22CTAATCTCCATTTGCCACTGAC 1208 chr3 58141834 58141855 +/− 22TAATCTCCATTTGCCACTGACC 1209 chr3 58141835 58141856 +/− 22AATCTCCATTTGCCACTGACCA 1210 chr3 58141836 58141857 +/− 22ATCTCCATTTGCCACTGACCAG 1211 chr3 58141837 58141858 +/− 22TCTCCATTTGCCACTGACCAGG 1212 chr3 58141838 58141859 +/− 22CTCCATTTGCCACTGACCAGGC 1213 chr3 58141839 58141860 +/− 22TCCATTTGCCACTGACCAGGCC 1214 chr3 58141840 58141861 +/− 22CCATTTGCCACTGACCAGGCCA 1215 chr3 58141841 58141862 +/− 22CATTTGCCACTGACCAGGCCAC 1216 chr3 58141842 58141863 +/− 22ATTTGCCACTGACCAGGCCACA 1217 chr3 58141843 58141864 +/− 22TTTGCCACTGACCAGGCCACAG 1218 chr3 58141844 58141865 +/− 22TTGCCACTGACCAGGCCACAGA 1219 chr3 58141845 58141866 +/− 22TGCCACTGACCAGGCCACAGAT 1220 chr3 58141846 58141867 +/− 22GCCACTGACCAGGCCACAGATG 1221 chr3 58141847 58141868 +/− 22CCACTGACCAGGCCACAGATGG 1222 chr3 58141848 58141869 +/− 22CACTGACCAGGCCACAGATGGG 1223 chr3 58141849 58141870 +/− 22ACTGACCAGGCCACAGATGGGG 1224 chr3 58141850 58141871 +/− 22CTGACCAGGCCACAGATGGGGA 1225 chr3 58141851 58141872 +/− 22TGACCAGGCCACAGATGGGGAA 1226 chr3 58141852 58141873 +/− 22GACCAGGCCACAGATGGGGAAG 1227 chr3 58141853 58141874 +/− 22ACCAGGCCACAGATGGGGAAGT 1228 chr3 58141854 58141875 +/− 22CCAGGCCACAGATGGGGAAGTC 1229 chr3 58141855 58141876 +/− 22CAGGCCACAGATGGGGAAGTCA 1230 chr3 58141856 58141877 +/− 22AGGCCACAGATGGGGAAGTCAC 1231 chr3 58141857 58141878 +/− 22GGCCACAGATGGGGAAGTCACA 1232 chr3 58141858 58141879 +/− 22GCCACAGATGGGGAAGTCACAG 1233 chr3 58141859 58141880 +/− 22CCACAGATGGGGAAGTCACAGC 1234 chr3 58141860 58141881 +/− 22CACAGATGGGGAAGTCACAGCC 1235 chr3 58141861 58141882 +/− 22ACAGATGGGGAAGTCACAGCCG 1236 chr3 58141862 58141883 +/− 22CAGATGGGGAAGTCACAGCCGT 1237 chr3 58141863 58141884 +/− 22AGATGGGGAAGTCACAGCCGTG 1238 chr3 58141864 58141885 +/− 22GATGGGGAAGTCACAGCCGTGG 1239 chr3 58141865 58141886 +/− 22ATGGGGAAGTCACAGCCGTGGA 1240 chr3 58141866 58141887 +/− 22TGGGGAAGTCACAGCCGTGGAG 1241 chr3 58141867 58141888 +/− 22GGGGAAGTCACAGCCGTGGAGG 1242 chr3 58141868 58141889 +/− 22GGGAAGTCACAGCCGTGGAGGA 1243 chr3 58141869 58141890 +/− 22GGAAGTCACAGCCGTGGAGGAG 1244 chr3 58141870 58141891 +/− 22GAAGTCACAGCCGTGGAGGAGG 1245 chr3 58141871 58141892 +/− 22AAGTCACAGCCGTGGAGGAGGC 1246 chr3 58141872 58141893 +/− 22AGTCACAGCCGTGGAGGAGGCA 1247 chr3 58141873 58141894 +/− 22GTCACAGCCGTGGAGGAGGCAC 1248 chr3 58141874 58141895 +/− 22TCACAGCCGTGGAGGAGGCACC 1249 chr3 58141875 58141896 +/− 22CACAGCCGTGGAGGAGGCACCG 1250 chr3 58141876 58141897 +/− 22ACAGCCGTGGAGGAGGCACCGG 1251 chr3 58141877 58141898 +/− 22CAGCCGTGGAGGAGGCACCGGT 1252 chr3 58141878 58141899 +/− 22AGCCGTGGAGGAGGCACCGGTA 1253 chr3 58141879 58141900 +/− 22GCCGTGGAGGAGGCACCGGTAA 1254 chr3 58141880 58141901 +/− 22CCGTGGAGGAGGCACCGGTAAA 1255 chr3 58141881 58141902 +/− 22CGTGGAGGAGGCACCGGTAAAT 1256 chr3 58141882 58141903 +/− 22GTGGAGGAGGCACCGGTAAATG 1257 chr3 58141883 58141904 +/− 22TGGAGGAGGCACCGGTAAATGC 1258 chr3 58141884 58141905 +/− 22GGAGGAGGCACCGGTAAATGCA 1259 chr3 58141885 58141906 +/− 22GAGGAGGCACCGGTAAATGCAT 1260 chr3 58141886 58141907 +/− 22AGGAGGCACCGGTAAATGCATG 1261 chr3 58141887 58141908 +/− 22GGAGGCACCGGTAAATGCATGT 1262 chr3 58141888 58141909 +/− 22GAGGCACCGGTAAATGCATGTC 1263 chr3 58141889 58141910 +/− 22AGGCACCGGTAAATGCATGTCC 1264 chr3 58141890 58141911 +/− 22GGCACCGGTAAATGCATGTCCC 1265 chr3 58141891 58141912 +/− 22GCACCGGTAAATGCATGTCCCC 1266 chr3 58141892 58141913 +/− 22CACCGGTAAATGCATGTCCCCC 1267 chr3 58141893 58141914 +/− 22ACCGGTAAATGCATGTCCCCCT 1268 chr3 58141894 58141915 +/− 22CCGGTAAATGCATGTCCCCCTG 1269 chr3 58141895 58141916 +/− 22CGGTAAATGCATGTCCCCCTGG 1270 chr3 58141896 58141917 +/− 22GGTAAATGCATGTCCCCCTGGA 1271 chr3 58141897 58141918 +/− 22GTAAATGCATGTCCCCCTGGAT 1272 chr3 58141898 58141919 +/− 22TAAATGCATGTCCCCCTGGATT 1273 chr3 58141899 58141920 +/− 22AAATGCATGTCCCCCTGGATTC 1274 chr3 58141900 58141921 +/− 22AATGCATGTCCCCCTGGATTCA 1275 chr3 58141901 58141922 +/− 22ATGCATGTCCCCCTGGATTCAG 1276 chr3 58141902 58141923 +/− 22TGCATGTCCCCCTGGATTCAGG 1277 chr3 58141903 58141924 +/− 22GCATGTCCCCCTGGATTCAGGC 1278 chr3 58141904 58141925 +/− 22CATGTCCCCCTGGATTCAGGCC 1279 chr3 58141905 58141926 +/− 22ATGTCCCCCTGGATTCAGGCCC 1280 chr3 58141906 58141927 +/− 22TGTCCCCCTGGATTCAGGCCCT 1281 chr3 58141907 58141928 +/− 22GTCCCCCTGGATTCAGGCCCTG 1282 chr3 58141908 58141929 +/− 22TCCCCCTGGATTCAGGCCCTGG 1283 chr3 58141909 58141930 +/− 22CCCCCTGGATTCAGGCCCTGGG 1284 chr3 58141910 58141931 +/− 22CCCCTGGATTCAGGCCCTGGGT 1285 chr3 58141911 58141932 +/− 22CCCTGGATTCAGGCCCTGGGTA 1286 chr3 58141912 58141933 +/− 22CCTGGATTCAGGCCCTGGGTAC 1287 chr3 58141913 58141934 +/− 22CTGGATTCAGGCCCTGGGTACA 1288 chr3 58141914 58141935 +/− 22TGGATTCAGGCCCTGGGTACAA 1289 chr3 58141915 58141936 +/− 22GGATTCAGGCCCTGGGTACAAT 1290 chr3 58141916 58141937 +/− 22GATTCAGGCCCTGGGTACAATT 1291 chr3 58141917 58141938 +/− 22ATTCAGGCCCTGGGTACAATTT 1292 chr3 58141918 58141939 +/− 22TTCAGGCCCTGGGTACAATTTT 1293 chr3 58141919 58141940 +/− 22TCAGGCCCTGGGTACAATTTTG 1294 chr3 58141920 58141941 +/− 22CAGGCCCTGGGTACAATTTTGG 1295 chr3 58141921 58141942 +/− 22AGGCCCTGGGTACAATTTTGGT 1296 chr3 58141922 58141943 +/− 22GGCCCTGGGTACAATTTTGGTT 1297 chr3 58141923 58141944 +/− 22GCCCTGGGTACAATTTTGGTTT 1298 chr3 58141924 58141945 +/− 22CCCTGGGTACAATTTTGGTTTT 1299 chr3 58141925 58141946 +/− 22CCTGGGTACAATTTTGGTTTTT 1300 chr3 58141926 58141947 +/− 22CTGGGTACAATTTTGGTTTTTT 1301 chr3 58141927 58141948 +/− 22TGGGTACAATTTTGGTTTTTTC 1302 chr3 58141928 58141949 +/− 22GGGTACAATTTTGGTTTTTTCC 1303 chr3 58141929 58141950 +/− 22GGTACAATTTTGGTTTTTTCCT 1304 chr3 58141930 58141951 +/− 22GTACAATTTTGGTTTTTTCCTT 1305 chr3 58141931 58141952 +/− 22TACAATTTTGGTTTTTTCCTTT 1306 chr3 58141932 58141953 +/− 22ACAATTTTGGTTTTTTCCTTTT 1307 chr3 58141933 58141954 +/− 22CAATTTTGGTTTTTTCCTTTTT 1308 chr3 58141934 58141955 +/− 22AATTTTGGTTTTTTCCTTTTTG 1309 chr3 58141935 58141956 +/− 22ATTTTGGTTTTTTCCTTTTTGT 1310 chr3 58141936 58141957 +/− 22TTTTGGTTTTTTCCTTTTTGTG 1311 chr3 58141937 58141958 +/− 22TTTGGTTTTTTCCTTTTTGTGT 1312 chr3 58141938 58141959 +/− 22TTGGTTTTTTCCTTTTTGTGTT 1313 chr3 58141939 58141960 +/− 22TGGTTTTTTCCTTTTTGTGTTT 1314 chr3 58141940 58141961 +/− 22GGTTTTTTCCTTTTTGTGTTTC 1315 chr3 58141941 58141962 +/− 22GTTTTTTCCTTTTTGTGTTTCT 1316 chr3 58141942 58141963 +/− 22TTTTTTCCTTTTTGTGTTTCTG 1317 chr3 58141943 58141964 +/− 22TTTTTCCTTTTTGTGTTTCTGT 1318 chr3 58141944 58141965 +/− 22TTTTCCTTTTTGTGTTTCTGTG 1319 chr3 58141945 58141966 +/− 22TTTCCTTTTTGTGTTTCTGTGT 1320 chr3 58141946 58141967 +/− 22TTCCTTTTTGTGTTTCTGTGTT 1321 chr3 58141947 58141968 +/− 22TCCTTTTTGTGTTTCTGTGTTT 1322 chr3 58141948 58141969 +/− 22CCTTTTTGTGTTTCTGTGTTTA 1323 chr3 58141949 58141970 +/− 22CTTTTTGTGTTTCTGTGTTTAC 1324 chr3 58141950 58141971 +/− 22TTTTTGTGTTTCTGTGTTTACT 1325 chr3 58141951 58141972 +/− 22TTTTGTGTTTCTGTGTTTACTC 1326 chr3 58141952 58141973 +/− 22TTTGTGTTTCTGTGTTTACTCA 1327 chr3 58141953 58141974 +/− 22TTGTGTTTCTGTGTTTACTCAG 1328 chr3 58141954 58141975 +/− 22TGTGTTTCTGTGTTTACTCAGC 1329 chr3 58141955 58141976 +/− 22GTGTTTCTGTGTTTACTCAGCC 1330 chr3 58141956 58141977 +/− 22TGTTTCTGTGTTTACTCAGCCT 1331 chr3 58141957 58141978 +/− 22GTTTCTGTGTTTACTCAGCCTT 1332 chr3 58141958 58141979 +/− 22TTTCTGTGTTTACTCAGCCTTC 1333 chr3 58141959 58141980 +/− 22TTCTGTGTTTACTCAGCCTTCA 1334 chr3 58141960 58141981 +/− 22TCTGTGTTTACTCAGCCTTCAT 1335 chr3 58141961 58141982 +/− 22CTGTGTTTACTCAGCCTTCATT 1336 chr3 58141962 58141983 +/− 22TGTGTTTACTCAGCCTTCATTT 1337 chr3 58141963 58141984 +/− 22GTGTTTACTCAGCCTTCATTTC 1338 chr3 58141964 58141985 +/− 22TGTTTACTCAGCCTTCATTTCA 1339 chr3 58141965 58141986 +/− 22GTTTACTCAGCCTTCATTTCAG 1340 chr3 58141966 58141987 +/− 22TTTACTCAGCCTTCATTTCAGA 1341 chr3 58141967 58141988 +/− 22TTACTCAGCCTTCATTTCAGAA 1342 chr3 58141968 58141989 +/− 22TACTCAGCCTTCATTTCAGAAA 1343 chr3 58141969 58141990 +/− 22ACTCAGCCTTCATTTCAGAAAA 1344 chr3 58141970 58141991 +/− 22CTCAGCCTTCATTTCAGAAAAT 1345 chr3 58141971 58141992 +/− 22TCAGCCTTCATTTCAGAAAATC 1346 chr3 58141972 58141993 +/− 22CAGCCTTCATTTCAGAAAATCT 1347 chr3 58141973 58141994 +/− 22AGCCTTCATTTCAGAAAATCTG 1348 chr3 58141974 58141995 +/− 22GCCTTCATTTCAGAAAATCTGC 1349 chr3 58141975 58141996 +/− 22CCTTCATTTCAGAAAATCTGCC 1350 chr3 58141976 58141997 +/− 22CTTCATTTCAGAAAATCTGCCA 1351 chr3 58141977 58141998 +/− 22TTCATTTCAGAAAATCTGCCAT 1352 chr3 58141978 58141999 +/− 22TCATTTCAGAAAATCTGCCATC 1353 chr3 58141979 58142000 +/− 22CATTTCAGAAAATCTGCCATCT 1354 chr3 58141980 58142001 +/− 22ATTTCAGAAAATCTGCCATCTG 1355 chr3 58141981 58142002 +/− 22TTTCAGAAAATCTGCCATCTGC 1356 chr3 58141982 58142003 +/− 22TTCAGAAAATCTGCCATCTGCT 1357 chr3 58141983 58142004 +/− 22TCAGAAAATCTGCCATCTGCTT 1358 chr3 58141984 58142005 +/− 22CAGAAAATCTGCCATCTGCTTC 1359 chr3 58141985 58142006 +/− 22AGAAAATCTGCCATCTGCTTCT 1360 chr3 58141986 58142007 +/− 22GAAAATCTGCCATCTGCTTCTG 1361 chr3 58141987 58142008 +/− 22AAAATCTGCCATCTGCTTCTGG 1362 chr3 58141988 58142009 +/− 22AAATCTGCCATCTGCTTCTGGG 1363 chr3 58141989 58142010 +/− 22AATCTGCCATCTGCTTCTGGGA 1364 chr3 58141990 58142011 +/− 22ATCTGCCATCTGCTTCTGGGAT 1365 chr3 58141991 58142012 +/− 22TCTGCCATCTGCTTCTGGGATT 1366 chr3 58141992 58142013 +/− 22CTGCCATCTGCTTCTGGGATTG 1367 chr3 58141993 58142014 +/− 22TGCCATCTGCTTCTGGGATTGC 1368 chr3 58141994 58142015 +/− 22GCCATCTGCTTCTGGGATTGCT 1369 chr3 58141995 58142016 +/− 22CCATCTGCTTCTGGGATTGCTT 1370 chr3 58141996 58142017 +/− 22CATCTGCTTCTGGGATTGCTTA 1371 chr3 58141997 58142018 +/− 22ATCTGCTTCTGGGATTGCTTAA 1372 chr3 58141998 58142019 +/− 22TCTGCTTCTGGGATTGCTTAAG 1373 chr3 58141999 58142020 +/− 22CTGCTTCTGGGATTGCTTAAGC 1374 chr3 58142000 58142021 +/− 22TGCTTCTGGGATTGCTTAAGCC 1375 chr3 58142001 58142022 +/− 22GCTTCTGGGATTGCTTAAGCCC 1376 chr3 58142002 58142023 +/− 22CTTCTGGGATTGCTTAAGCCCT 1377 chr3 58142003 58142024 +/− 22TTCTGGGATTGCTTAAGCCCTG 1378 chr3 58142004 58142025 +/− 22TCTGGGATTGCTTAAGCCCTGT 1379 chr3 58142005 58142026 +/− 22CTGGGATTGCTTAAGCCCTGTG 1380 chr3 58142006 58142027 +/− 22TGGGATTGCTTAAGCCCTGTGG 1381 chr3 58142007 58142028 +/− 22GGGATTGCTTAAGCCCTGTGGG 1382 chr3 58142008 58142029 +/− 22GGATTGCTTAAGCCCTGTGGGT 1383 chr3 58142009 58142030 +/− 22GATTGCTTAAGCCCTGTGGGTG 1384 chr3 58142010 58142031 +/− 22ATTGCTTAAGCCCTGTGGGTGT 1385 chr3 58142011 58142032 +/− 22TTGCTTAAGCCCTGTGGGTGTC 1386 chr3 58142012 58142033 +/− 22TGCTTAAGCCCTGTGGGTGTCC 1387 chr3 58142013 58142034 +/− 22GCTTAAGCCCTGTGGGTGTCCT 1388 chr3 58142014 58142035 +/− 22CTTAAGCCCTGTGGGTGTCCTG 1389 chr3 58142015 58142036 +/− 22TTAAGCCCTGTGGGTGTCCTGG 1390 chr3 58142016 58142037 +/− 22TAAGCCCTGTGGGTGTCCTGGT 1391 chr3 58142017 58142038 +/− 22AAGCCCTGTGGGTGTCCTGGTC 1392 chr3 58142018 58142039 +/− 22AGCCCTGTGGGTGTCCTGGTCA 1393 chr3 58142019 58142040 +/− 22GCCCTGTGGGTGTCCTGGTCAT 1394 chr3 58142020 58142041 +/− 22CCCTGTGGGTGTCCTGGTCATT 1395 chr3 58142021 58142042 +/− 22CCTGTGGGTGTCCTGGTCATTG 1396 chr3 58142022 58142043 +/− 22CTGTGGGTGTCCTGGTCATTGG 1397 chr3 58142023 58142044 +/− 22TGTGGGTGTCCTGGTCATTGGT 1398

Tables 9-15 comprise some additional example oligonucleotide sequencesof variable sequence lengths that may be used to induce an isoformswitch or modulate (e.g., inhibit or enhance) the biological activity ofa specific isoform of one or several of the genes described above orelsewhere herein (e.g., genes comprising one or more of NEDD4L (ENV2),MAP3K7 (ENV3), NFYA (ENV11), ESYT2 (ENV21), MARK2 (ENV18), ST7 (ENV19),ARVCF (ENV22), SYTL2 (ENV17), R3HDM1 (ENV23), COL4A3BP (ENV9), TANGO2(ENV6), SEPT9 (ENV15), ROBO1 (ENV4), FAM122B (ENV5), CD47 (ENV13), LSR(ENV20), PBX1 (ENV16), EPB41 (ENV14), ADAM15 (ENV7), EPB41L1 (ENV8),ABI1 (ENV10), FLNB (ENV1), CTNND1 (ENV12), GPR160 (ENV24), ITGB3BP(ENV25), INCENP (ENV26), DENND1B (ENV27), CA12 (ENV28).

As discussed above, oligonucleotide sequences comprised in a table maybe specific for a single target, or for more than one target. In somecases, oligonucleotide sequences comprised in more than one tables arespecific for a single target. For example, oligonucleotide sequencescomprised in Tables 9-15 may be specific for a single target. The targetmay be the same as or differ from the target which the oligonucleotidesequences comprised in Tables 2-8 are specific for. The target may be agene selected from genes described above or elsewhere herein.

TABLE 9 16-mer target-specific SEQ ID CHR START END STRAND Kmer SEQUENCENO: chr18 58335318 58335333 +/− 16 GGTCATCAGCGACTGC 1399 chr18 5833531958335334 +/− 16 GTCATCAGCGACTGCT 1400 chr18 58335320 58335335 +/− 16TCATCAGCGACTGCTG 1401 chr18 58335321 58335336 +/− 16 CATCAGCGACTGCTGG1402 chr18 58335322 58335337 +/− 16 ATCAGCGACTGCTGGC 1403 chr18 5833532358335338 +/− 16 TCAGCGACTGCTGGCT 1404 chr18 58335324 58335339 +/− 16CAGCGACTGCTGGCTT 1405 chr18 58335325 58335340 +/− 16 AGCGACTGCTGGCTTT1406 chr18 58335326 58335341 +/− 16 GCGACTGCTGGCTTTG 1407 chr18 5833532758335342 +/− 16 CGACTGCTGGCTTTGT 1408 chr18 58335328 58335343 +/− 16GACTGCTGGCTTTGTC 1409 chr18 58335329 58335344 +/− 16 ACTGCTGGCTTTGTCT1410 chr18 58335330 58335345 +/− 16 CTGCTGGCTTTGTCTG 1411 chr18 5833533158335346 +/− 16 TGCTGGCTTTGTCTGG 1412 chr18 58335332 58335347 +/− 16GCTGGCTTTGTCTGGA 1413 chr18 58335333 58335348 +/− 16 CTGGCTTTGTCTGGAT1414 chr18 58335334 58335349 +/− 16 TGGCTTTGTCTGGATA 1415 chr18 5833533558335350 +/− 16 GGCTTTGTCTGGATAG 1416 chr18 58335336 58335351 +/− 16GCTTTGTCTGGATAGG 1417 chr18 58335337 58335352 +/− 16 CTTTGTCTGGATAGGG1418 chr18 58335338 58335353 +/− 16 TTTGTCTGGATAGGGT 1419 chr18 5833533958335354 +/− 16 TTGTCTGGATAGGGTG 1420 chr18 58335340 58335355 +/− 16TGTCTGGATAGGGTGG 1421 chr18 58335341 58335356 +/− 16 GTCTGGATAGGGTGGG1422 chr18 58335342 58335357 +/− 16 TCTGGATAGGGTGGGT 1423 chr18 5833534358335358 +/− 16 CTGGATAGGGTGGGTT 1424 chr18 58335344 58335359 +/− 16TGGATAGGGTGGGTTT 1425 chr18 58335345 58335360 +/− 16 GGATAGGGTGGGTTTC1426 chr18 58335346 58335361 +/− 16 GATAGGGTGGGTTTCA 1427 chr18 5833534758335362 +/− 16 ATAGGGTGGGTTTCAG 1428 chr18 58335348 58335363 +/− 16TAGGGTGGGTTTCAGG 1429 chr18 58335349 58335364 +/− 16 AGGGTGGGTTTCAGGG1430 chr18 58335350 58335365 +/− 16 GGGTGGGTTTCAGGGA 1431 chr18 5833535158335366 +/− 16 GGTGGGTTTCAGGGAT 1432 chr18 58335352 58335367 +/− 16GTGGGTTTCAGGGATT 1433 chr18 58335353 58335368 +/− 16 TGGGTTTCAGGGATTC1434 chr18 58335354 58335369 +/− 16 GGGTTTCAGGGATTCT 1435 chr18 5833535558335370 +/− 16 GGTTTCAGGGATTCTG 1436 chr18 58335356 58335371 +/− 16GTTTCAGGGATTCTGA 1437 chr18 58335357 58335372 +/− 16 TTTCAGGGATTCTGAT1438 chr18 58335358 58335373 +/− 16 TTCAGGGATTCTGATC 1439 chr18 5833535958335374 +/− 16 TCAGGGATTCTGATCT 1440 chr18 58335360 58335375 +/− 16CAGGGATTCTGATCTC 1441 chr18 58335361 58335376 +/− 16 AGGGATTCTGATCTCA1442 chr18 58335362 58335377 +/− 16 GGGATTCTGATCTCAC 1443 chr18 5833536358335378 +/− 16 GGATTCTGATCTCACG 1444 chr18 58335364 58335379 +/− 16GATTCTGATCTCACGT 1445 chr18 58335365 58335380 +/− 16 ATTCTGATCTCACGTC1446 chr18 58335366 58335381 +/− 16 TTCTGATCTCACGTCA 1447 chr18 5833536758335382 +/− 16 TCTGATCTCACGTCAC 1448 chr18 58335368 58335383 +/− 16CTGATCTCACGTCACC 1449 chr18 58335369 58335384 +/− 16 TGATCTCACGTCACCT1450 chr18 58335370 58335385 +/− 16 GATCTCACGTCACCTG 1451 chr18 5833537158335386 +/− 16 ATCTCACGTCACCTGC 1452 chr18 58335372 58335387 +/− 16TCTCACGTCACCTGCC 1453 chr18 58335373 58335388 +/− 16 CTCACGTCACCTGCCT1454 chr18 58335374 58335389 +/− 16 TCACGTCACCTGCCTT 1455 chr18 5833537558335390 +/− 16 CACGTCACCTGCCTTA 1456 chr18 58335376 58335391 +/− 16ACGTCACCTGCCTTAC 1457 chr18 58335377 58335392 +/− 16 CGTCACCTGCCTTACA1458 chr18 58335378 58335393 +/− 16 GTCACCTGCCTTACAG 1459 chr18 5833537958335394 +/− 16 TCACCTGCCTTACAGC 1460 chr18 58335380 58335395 +/− 16CACCTGCCTTACAGCG 1461 chr18 58335381 58335396 +/− 16 ACCTGCCTTACAGCGC1462 chr18 58335382 58335397 +/− 16 CCTGCCTTACAGCGCT 1463 chr18 5833538358335398 +/− 16 CTGCCTTACAGCGCTG 1464 chr18 58335384 58335399 +/− 16TGCCTTACAGCGCTGC 1465 chr18 58335385 58335400 +/− 16 GCCTTACAGCGCTGCC1466 chr18 58335386 58335401 +/− 16 CCTTACAGCGCTGCCA 1467 chr18 5833538758335402 +/− 16 CTTACAGCGCTGCCAC 1468 chr18 58335388 58335403 +/− 16TTACAGCGCTGCCACA 1469 chr18 58335389 58335404 +/− 16 TACAGCGCTGCCACAG1470 chr18 58335390 58335405 +/− 16 ACAGCGCTGCCACAGC 1471 chr18 5833539158335406 +/− 16 CAGCGCTGCCACAGCA 1472 chr18 58335392 58335407 +/− 16AGCGCTGCCACAGCAG 1473 chr18 58335393 58335408 +/− 16 GCGCTGCCACAGCAGT1474 chr18 58335394 58335409 +/− 16 CGCTGCCACAGCAGTG 1475 chr18 5833539558335410 +/− 16 GCTGCCACAGCAGTGG 1476 chr18 58335396 58335411 +/− 16CTGCCACAGCAGTGGG 1477 chr18 58335397 58335412 +/− 16 TGCCACAGCAGTGGGC1478 chr18 58335398 58335413 +/− 16 GCCACAGCAGTGGGCC 1479 chr18 5833539958335414 +/− 16 CCACAGCAGTGGGCCC 1480 chr18 58335400 58335415 +/− 16CACAGCAGTGGGCCCT 1481 chr18 58335401 58335416 +/− 16 ACAGCAGTGGGCCCTG1482 chr18 58335402 58335417 +/− 16 CAGCAGTGGGCCCTGA 1483 chr18 5833540358335418 +/− 16 AGCAGTGGGCCCTGAT 1484 chr18 58335404 58335419 +/− 16GCAGTGGGCCCTGATT 1485 chr18 58335405 58335420 +/− 16 CAGTGGGCCCTGATTC1486 chr18 58335406 58335421 +/− 16 AGTGGGCCCTGATTCA 1487 chr18 5833540758335422 +/− 16 GTGGGCCCTGATTCAG 1488 chr18 58335408 58335423 +/− 16TGGGCCCTGATTCAGA 1489 chr18 58335409 58335424 +/− 16 GGGCCCTGATTCAGAC1490 chr18 58335410 58335425 +/− 16 GGCCCTGATTCAGACA 1491 chr18 5833541158335426 +/− 16 GCCCTGATTCAGACAG 1492 chr18 58335412 58335427 +/− 16CCCTGATTCAGACAGC 1493 chr18 58335413 58335428 +/− 16 CCTGATTCAGACAGCA1494 chr18 58335414 58335429 +/− 16 CTGATTCAGACAGCAG 1495 chr18 5833541558335430 +/− 16 TGATTCAGACAGCAGG 1496 chr18 58335317 58335332 +/− 16TGGTCATCAGCGACTG 1497 chr18 58335416 58335431 +/− 16 GATTCAGACAGCAGGG1498 chr18 58335417 58335432 +/− 16 ATTCAGACAGCAGGGG 1499 chr18 5833541858335433 +/− 16 TTCAGACAGCAGGGGG 1500 chr18 58335419 58335434 +/− 16TCAGACAGCAGGGGGT 1501 chr18 58335420 58335435 +/− 16 CAGACAGCAGGGGGTC1502 chr18 58335421 58335436 +/− 16 AGACAGCAGGGGGTCA 1503 chr18 5833542258335437 +/− 16 GACAGCAGGGGGTCAT 1504 chr18 58335423 58335438 +/− 16ACAGCAGGGGGTCATC 1505 chr18 58335424 58335439 +/− 16 CAGCAGGGGGTCATCC1506 chr18 58335425 58335440 +/− 16 AGCAGGGGGTCATCCC 1507 chr18 5833542658335441 +/− 16 GCAGGGGGTCATCCCC 1508 chr18 58335427 58335442 +/− 16CAGGGGGTCATCCCCT 1509 chr18 58335428 58335443 +/− 16 AGGGGGTCATCCCCTA1510 chr18 58335429 58335444 +/− 16 GGGGGTCATCCCCTAA 1511 chr18 5833543058335445 +/− 16 GGGGTCATCCCCTAAG 1512 chr18 58335431 58335446 +/− 16GGGTCATCCCCTAAGT 1513 chr18 58335432 58335447 +/− 16 GGTCATCCCCTAAGTG1514

TABLE 10 17-mer target-specific ASOs SEQ ID CHR START END STRAND KmerSEQUENCE NO: chr18 58335318 58335334 +/− 17 GGTCATCAGCGACTGCT 1515 chr1858335319 58335335 +/− 17 GTCATCAGCGACTGCTG 1516 chr18 58335320 58335336+/− 17 TCATCAGCGACTGCTGG 1517 chr18 58335321 58335337 +/− 17CATCAGCGACTGCTGGC 1518 chr18 58335322 58335338 +/− 17 ATCAGCGACTGCTGGCT1519 chr18 58335323 58335339 +/− 17 TCAGCGACTGCTGGCTT 1520 chr1858335324 58335340 +/− 17 CAGCGACTGCTGGCTTT 1521 chr18 58335325 58335341+/− 17 AGCGACTGCTGGCTTTG 1522 chr18 58335326 58335342 +/− 17GCGACTGCTGGCTTTGT 1523 chr18 58335327 58335343 +/− 17 CGACTGCTGGCTTTGTC1524 chr18 58335328 58335344 +/− 17 GACTGCTGGCTTTGTCT 1525 chr1858335329 58335345 +/− 17 ACTGCTGGCTTTGTCTG 1526 chr18 58335330 58335346+/− 17 CTGCTGGCTTTGTCTGG 1527 chr18 58335331 58335347 +/− 17TGCTGGCTTTGTCTGGA 1528 chr18 58335332 58335348 +/− 17 GCTGGCTTTGTCTGGAT1529 chr18 58335333 58335349 +/− 17 CTGGCTTTGTCTGGATA 1530 chr1858335334 58335350 +/− 17 TGGCTTTGTCTGGATAG 1531 chr18 58335335 58335351+/− 17 GGCTTTGTCTGGATAGG 1532 chr18 58335336 58335352 +/− 17GCTTTGTCTGGATAGGG 1533 chr18 58335337 58335353 +/− 17 CTTTGTCTGGATAGGGT1534 chr18 58335338 58335354 +/− 17 TTTGTCTGGATAGGGTG 1535 chr1858335339 58335355 +/− 17 TTGTCTGGATAGGGTGG 1536 chr18 58335340 58335356+/− 17 TGTCTGGATAGGGTGGG 1537 chr18 58335341 58335357 +/− 17GTCTGGATAGGGTGGGT 1538 chr18 58335342 58335358 +/− 17 TCTGGATAGGGTGGGTT1539 chr18 58335343 58335359 +/− 17 CTGGATAGGGTGGGTTT 1540 chr1858335344 58335360 +/− 17 TGGATAGGGTGGGTTTC 1541 chr18 58335345 58335361+/− 17 GGATAGGGTGGGTTTCA 1542 chr18 58335346 58335362 +/− 17GATAGGGTGGGTTTCAG 1543 chr18 58335347 58335363 +/− 17 ATAGGGTGGGTTTCAGG1544 chr18 58335348 58335364 +/− 17 TAGGGTGGGTTTCAGGG 1545 chr1858335349 58335365 +/− 17 AGGGTGGGTTTCAGGGA 1546 chr18 58335350 58335366+/− 17 GGGTGGGTTTCAGGGAT 1547 chr18 58335351 58335367 +/− 17GGTGGGTTTCAGGGATT 1548 chr18 58335352 58335368 +/− 17 GTGGGTTTCAGGGATTC1549 chr18 58335353 58335369 +/− 17 TGGGTTTCAGGGATTCT 1550 chr1858335354 58335370 +/− 17 GGGTTTCAGGGATTCTG 1551 chr18 58335355 58335371+/− 17 GGTTTCAGGGATTCTGA 1552 chr18 58335356 58335372 +/− 17GTTTCAGGGATTCTGAT 1553 chr18 58335357 58335373 +/− 17 TTTCAGGGATTCTGATC1554 chr18 58335358 58335374 +/− 17 TTCAGGGATTCTGATCT 1555 chr1858335359 58335375 +/− 17 TCAGGGATTCTGATCTC 1556 chr18 58335360 58335376+/− 17 CAGGGATTCTGATCTCA 1557 chr18 58335361 58335377 +/− 17AGGGATTCTGATCTCAC 1558 chr18 58335362 58335378 +/− 17 GGGATTCTGATCTCACG1559 chr18 58335363 58335379 +/− 17 GGATTCTGATCTCACGT 1560 chr1858335364 58335380 +/− 17 GATTCTGATCTCACGTC 1561 chr18 58335365 58335381+/− 17 ATTCTGATCTCACGTCA 1562 chr18 58335366 58335382 +/− 17TTCTGATCTCACGTCAC 1563 chr18 58335367 58335383 +/− 17 TCTGATCTCACGTCACC1564 chr18 58335368 58335384 +/− 17 CTGATCTCACGTCACCT 1565 chr1858335369 58335385 +/− 17 TGATCTCACGTCACCTG 1566 chr18 58335370 58335386+/− 17 GATCTCACGTCACCTGC 1567 chr18 58335371 58335387 +/− 17ATCTCACGTCACCTGCC 1568 chr18 58335372 58335388 +/− 17 TCTCACGTCACCTGCCT1569 chr18 58335373 58335389 +/− 17 CTCACGTCACCTGCCTT 1570 chr1858335374 58335390 +/− 17 TCACGTCACCTGCCTTA 1571 chr18 58335375 58335391+/− 17 CACGTCACCTGCCTTAC 1572 chr18 58335376 58335392 +/− 17ACGTCACCTGCCTTACA 1573 chr18 58335377 58335393 +/− 17 CGTCACCTGCCTTACAG1574 chr18 58335378 58335394 +/− 17 GTCACCTGCCTTACAGC 1575 chr1858335379 58335395 +/− 17 TCACCTGCCTTACAGCG 1576 chr18 58335380 58335396+/− 17 CACCTGCCTTACAGCGC 1577 chr18 58335381 58335397 +/− 17ACCTGCCTTACAGCGCT 1578 chr18 58335382 58335398 +/− 17 CCTGCCTTACAGCGCTG1579 chr18 58335383 58335399 +/− 17 CTGCCTTACAGCGCTGC 1580 chr1858335384 58335400 +/− 17 TGCCTTACAGCGCTGCC 1581 chr18 58335385 58335401+/− 17 GCCTTACAGCGCTGCCA 1582 chr18 58335386 58335402 +/− 17CCTTACAGCGCTGCCAC 1583 chr18 58335387 58335403 +/− 17 CTTACAGCGCTGCCACA1584 chr18 58335388 58335404 +/− 17 TTACAGCGCTGCCACAG 1585 chr1858335389 58335405 +/− 17 TACAGCGCTGCCACAGC 1586 chr18 58335390 58335406+/− 17 ACAGCGCTGCCACAGCA 1587 chr18 58335391 58335407 +/− 17CAGCGCTGCCACAGCAG 1588 chr18 58335392 58335408 +/− 17 AGCGCTGCCACAGCAGT1589 chr18 58335393 58335409 +/− 17 GCGCTGCCACAGCAGTG 1590 chr1858335394 58335410 +/− 17 CGCTGCCACAGCAGTGG 1591 chr18 58335395 58335411+/− 17 GCTGCCACAGCAGTGGG 1592 chr18 58335396 58335412 +/− 17CTGCCACAGCAGTGGGC 1593 chr18 58335397 58335413 +/− 17 TGCCACAGCAGTGGGCC1594 chr18 58335398 58335414 +/− 17 GCCACAGCAGTGGGCCC 1595 chr1858335399 58335415 +/− 17 CCACAGCAGTGGGCCCT 1596 chr18 58335400 58335416+/− 17 CACAGCAGTGGGCCCTG 1597 chr18 58335401 58335417 +/− 17ACAGCAGTGGGCCCTGA 1598 chr18 58335402 58335418 +/− 17 CAGCAGTGGGCCCTGAT1599 chr18 58335403 58335419 +/− 17 AGCAGTGGGCCCTGATT 1600 chr1858335404 58335420 +/− 17 GCAGTGGGCCCTGATTC 1601 chr18 58335405 58335421+/− 17 CAGTGGGCCCTGATTCA 1602 chr18 58335406 58335422 +/− 17AGTGGGCCCTGATTCAG 1603 chr18 58335407 58335423 +/− 17 GTGGGCCCTGATTCAGA1604 chr18 58335408 58335424 +/− 17 TGGGCCCTGATTCAGAC 1605 chr1858335409 58335425 +/− 17 GGGCCCTGATTCAGACA 1606 chr18 58335410 58335426+/− 17 GGCCCTGATTCAGACAG 1607 chr18 58335411 58335427 +/− 17GCCCTGATTCAGACAGC 1608 chr18 58335412 58335428 +/− 17 CCCTGATTCAGACAGCA1609 chr18 58335413 58335429 +/− 17 CCTGATTCAGACAGCAG 1610 chr1858335414 58335430 +/− 17 CTGATTCAGACAGCAGG 1611 chr18 58335317 58335333+/− 17 TGGTCATCAGCGACTGC 1612 chr18 58335415 58335431 +/− 17TGATTCAGACAGCAGGG 1613 chr18 58335416 58335432 +/− 17 GATTCAGACAGCAGGGG1614 chr18 58335417 58335433 +/− 17 ATTCAGACAGCAGGGGG 1615 chr1858335418 58335434 +/− 17 TTCAGACAGCAGGGGGT 1616 chr18 58335419 58335435+/− 17 TCAGACAGCAGGGGGTC 1617 chr18 58335420 58335436 +/− 17CAGACAGCAGGGGGTCA 1618 chr18 58335421 58335437 +/− 17 AGACAGCAGGGGGTCAT1619 chr18 58335422 58335438 +/− 17 GACAGCAGGGGGTCATC 1620 chr1858335423 58335439 +/− 17 ACAGCAGGGGGTCATCC 1621 chr18 58335424 58335440+/− 17 CAGCAGGGGGTCATCCC 1622 chr18 58335425 58335441 +/− 17AGCAGGGGGTCATCCCC 1623 chr18 58335426 58335442 +/− 17 GCAGGGGGTCATCCCCT1624 chr18 58335427 58335443 +/− 17 CAGGGGGTCATCCCCTA 1625 chr1858335428 58335444 +/− 17 AGGGGGTCATCCCCTAA 1626 chr18 58335429 58335445+/− 17 GGGGGTCATCCCCTAAG 1627 chr18 58335430 58335446 +/− 17GGGGTCATCCCCTAAGT 1628 chr18 58335431 58335447 +/− 17 GGGTCATCCCCTAAGTG1629

TABLE 11 18-mer target-specific ASOs SEQ ID CHR START END STRAND KmerSEQUENCE NO: chr18 58335318 58335335 +/− 18 GGTCATCAGCGACTGCTG 1630chr18 58335319 58335336 +/− 18 GTCATCAGCGACTGCTGG 1631 chr18 5833532058335337 +/− 18 TCATCAGCGACTGCTGGC 1632 chr18 58335321 58335338 +/− 18CATCAGCGACTGCTGGCT 1633 chr18 58335322 58335339 +/− 18ATCAGCGACTGCTGGCTT 1634 chr18 58335323 58335340 +/− 18TCAGCGACTGCTGGCTTT 1635 chr18 58335324 58335341 +/− 18CAGCGACTGCTGGCTTTG 1636 chr18 58335325 58335342 +/− 18AGCGACTGCTGGCTTTGT 1637 chr18 58335326 58335343 +/− 18GCGACTGCTGGCTTTGTC 1638 chr18 58335327 58335344 +/− 18CGACTGCTGGCTTTGTCT 1639 chr18 58335328 58335345 +/− 18GACTGCTGGCTTTGTCTG 1640 chr18 58335329 58335346 +/− 18ACTGCTGGCTTTGTCTGG 1641 chr18 58335330 58335347 +/− 18CTGCTGGCTTTGTCTGGA 1642 chr18 58335331 58335348 +/− 18TGCTGGCTTTGTCTGGAT 1643 chr18 58335332 58335349 +/− 18GCTGGCTTTGTCTGGATA 1644 chr18 58335333 58335350 +/− 18CTGGCTTTGTCTGGATAG 1645 chr18 58335334 58335351 +/− 18TGGCTTTGTCTGGATAGG 1646 chr18 58335335 58335352 +/− 18GGCTTTGTCTGGATAGGG 1647 chr18 58335336 58335353 +/− 18GCTTTGTCTGGATAGGGT 1648 chr18 58335337 58335354 +/− 18CTTTGTCTGGATAGGGTG 1649 chr18 58335338 58335355 +/− 18TTTGTCTGGATAGGGTGG 1650 chr18 58335339 58335356 +/− 18TTGTCTGGATAGGGTGGG 1651 chr18 58335340 58335357 +/− 18TGTCTGGATAGGGTGGGT 1652 chr18 58335341 58335358 +/− 18GTCTGGATAGGGTGGGTT 1653 chr18 58335342 58335359 +/− 18TCTGGATAGGGTGGGTTT 1654 chr18 58335343 58335360 +/− 18CTGGATAGGGTGGGTTTC 1655 chr18 58335344 58335361 +/− 18TGGATAGGGTGGGTTTCA 1656 chr18 58335345 58335362 +/− 18GGATAGGGTGGGTTTCAG 1657 chr18 58335346 58335363 +/− 18GATAGGGTGGGTTTCAGG 1658 chr18 58335347 58335364 +/− 18ATAGGGTGGGTTTCAGGG 1659 chr18 58335348 58335365 +/− 18TAGGGTGGGTTTCAGGGA 1660 chr18 58335349 58335366 +/− 18AGGGTGGGTTTCAGGGAT 1661 chr18 58335350 58335367 +/− 18GGGTGGGTTTCAGGGATT 1662 chr18 58335351 58335368 +/− 18GGTGGGTTTCAGGGATTC 1663 chr18 58335352 58335369 +/− 18GTGGGTTTCAGGGATTCT 1664 chr18 58335353 58335370 +/− 18TGGGTTTCAGGGATTCTG 1665 chr18 58335354 58335371 +/− 18GGGTTTCAGGGATTCTGA 1666 chr18 58335355 58335372 +/− 18GGTTTCAGGGATTCTGAT 1667 chr18 58335356 58335373 +/− 18GTTTCAGGGATTCTGATC 1668 chr18 58335357 58335374 +/− 18TTTCAGGGATTCTGATCT 1669 chr18 58335358 58335375 +/− 18TTCAGGGATTCTGATCTC 1670 chr18 58335359 58335376 +/− 18TCAGGGATTCTGATCTCA 1671 chr18 58335360 58335377 +/− 18CAGGGATTCTGATCTCAC 1672 chr18 58335361 58335378 +/− 18AGGGATTCTGATCTCACG 1673 chr18 58335362 58335379 +/− 18GGGATTCTGATCTCACGT 1674 chr18 58335363 58335380 +/− 18GGATTCTGATCTCACGTC 1675 chr18 58335364 58335381 +/− 18GATTCTGATCTCACGTCA 1676 chr18 58335365 58335382 +/− 18ATTCTGATCTCACGTCAC 1677 chr18 58335366 58335383 +/− 18TTCTGATCTCACGTCACC 1678 chr18 58335367 58335384 +/− 18TCTGATCTCACGTCACCT 1679 chr18 58335368 58335385 +/− 18CTGATCTCACGTCACCTG 1680 chr18 58335369 58335386 +/− 18TGATCTCACGTCACCTGC 1681 chr18 58335370 58335387 +/− 18GATCTCACGTCACCTGCC 1682 chr18 58335371 58335388 +/− 18ATCTCACGTCACCTGCCT 1683 chr18 58335372 58335389 +/− 18TCTCACGTCACCTGCCTT 1684 chr18 58335373 58335390 +/− 18CTCACGTCACCTGCCTTA 1685 chr18 58335374 58335391 +/− 18TCACGTCACCTGCCTTAC 1686 chr18 58335375 58335392 +/− 18CACGTCACCTGCCTTACA 1687 chr18 58335376 58335393 +/− 18ACGTCACCTGCCTTACAG 1688 chr18 58335377 58335394 +/− 18CGTCACCTGCCTTACAGC 1689 chr18 58335378 58335395 +/− 18GTCACCTGCCTTACAGCG 1690 chr18 58335379 58335396 +/− 18TCACCTGCCTTACAGCGC 1691 chr18 58335380 58335397 +/− 18CACCTGCCTTACAGCGCT 1692 chr18 58335381 58335398 +/− 18ACCTGCCTTACAGCGCTG 1693 chr18 58335382 58335399 +/− 18CCTGCCTTACAGCGCTGC 1694 chr18 58335383 58335400 +/− 18CTGCCTTACAGCGCTGCC 1695 chr18 58335384 58335401 +/− 18TGCCTTACAGCGCTGCCA 1696 chr18 58335385 58335402 +/− 18GCCTTACAGCGCTGCCAC 1697 chr18 58335386 58335403 +/− 18CCTTACAGCGCTGCCACA 1698 chr18 58335387 58335404 +/− 18CTTACAGCGCTGCCACAG 1699 chr18 58335388 58335405 +/− 18TTACAGCGCTGCCACAGC 1700 chr18 58335389 58335406 +/− 18TACAGCGCTGCCACAGCA 1701 chr18 58335390 58335407 +/− 18ACAGCGCTGCCACAGCAG 1702 chr18 58335391 58335408 +/− 18CAGCGCTGCCACAGCAGT 1703 chr18 58335392 58335409 +/− 18AGCGCTGCCACAGCAGTG 1704 chr18 58335393 58335410 +/− 18GCGCTGCCACAGCAGTGG 1705 chr18 58335394 58335411 +/− 18CGCTGCCACAGCAGTGGG 1706 chr18 58335395 58335412 +/− 18GCTGCCACAGCAGTGGGC 1707 chr18 58335396 58335413 +/− 18CTGCCACAGCAGTGGGCC 1708 chr18 58335397 58335414 +/− 18TGCCACAGCAGTGGGCCC 1709 chr18 58335398 58335415 +/− 18GCCACAGCAGTGGGCCCT 1710 chr18 58335399 58335416 +/− 18CCACAGCAGTGGGCCCTG 1711 chr18 58335400 58335417 +/− 18CACAGCAGTGGGCCCTGA 1712 chr18 58335401 58335418 +/− 18ACAGCAGTGGGCCCTGAT 1713 chr18 58335402 58335419 +/− 18CAGCAGTGGGCCCTGATT 1714 chr18 58335403 58335420 +/− 18AGCAGTGGGCCCTGATTC 1715 chr18 58335404 58335421 +/− 18GCAGTGGGCCCTGATTCA 1716 chr18 58335405 58335422 +/− 18CAGTGGGCCCTGATTCAG 1717 chr18 58335406 58335423 +/− 18AGTGGGCCCTGATTCAGA 1718 chr18 58335407 58335424 +/− 18GTGGGCCCTGATTCAGAC 1719 chr18 58335408 58335425 +/− 18TGGGCCCTGATTCAGACA 1720 chr18 58335409 58335426 +/− 18GGGCCCTGATTCAGACAG 1721 chr18 58335410 58335427 +/− 18GGCCCTGATTCAGACAGC 1722 chr18 58335411 58335428 +/− 18GCCCTGATTCAGACAGCA 1723 chr18 58335412 58335429 +/− 18CCCTGATTCAGACAGCAG 1724 chr18 58335413 58335430 +/− 18CCTGATTCAGACAGCAGG 1725 chr18 58335317 58335334 +/− 18TGGTCATCAGCGACTGCT 1726 chr18 58335414 58335431 +/− 18CTGATTCAGACAGCAGGG 1727 chr18 58335415 58335432 +/− 18TGATTCAGACAGCAGGGG 1728 chr18 58335416 58335433 +/− 18GATTCAGACAGCAGGGGG 1729 chr18 58335417 58335434 +/− 18ATTCAGACAGCAGGGGGT 1730 chr18 58335418 58335435 +/− 18TTCAGACAGCAGGGGGTC 1731 chr18 58335419 58335436 +/− 18TCAGACAGCAGGGGGTCA 1732 chr18 58335420 58335437 +/− 18CAGACAGCAGGGGGTCAT 1733 chr18 58335421 58335438 +/− 18AGACAGCAGGGGGTCATC 1734 chr18 58335422 58335439 +/− 18GACAGCAGGGGGTCATCC 1735 chr18 58335423 58335440 +/− 18ACAGCAGGGGGTCATCCC 1736 chr18 58335424 58335441 +/− 18CAGCAGGGGGTCATCCCC 1737 chr18 58335425 58335442 +/− 18AGCAGGGGGTCATCCCCT 1738 chr18 58335426 58335443 +/− 18GCAGGGGGTCATCCCCTA 1739 chr18 58335427 58335444 +/− 18CAGGGGGTCATCCCCTAA 1740 chr18 58335428 58335445 +/− 18AGGGGGTCATCCCCTAAG 1741 chr18 58335429 58335446 +/− 18GGGGGTCATCCCCTAAGT 1742 chr18 58335430 58335447 +/− 18GGGGTCATCCCCTAAGTG 1743

TABLE 12 19-mer target-specific ASOs SEQ ID CHR START END STRAND KmerSEQUENCE NO: chr18 58335318 58335336 +/− 19 GGTCATCAGCGACTGCTGG 1744chr18 58335319 58335337 +/− 19 GTCATCAGCGACTGCTGGC 1745 chr18 5833532058335338 +/− 19 TCATCAGCGACTGCTGGCT 1746 chr18 58335321 58335339 +/− 19CATCAGCGACTGCTGGCTT 1747 chr18 58335322 58335340 +/− 19ATCAGCGACTGCTGGCTTT 1748 chr18 58335323 58335341 +/− 19TCAGCGACTGCTGGCTTTG 1749 chr18 58335324 58335342 +/− 19CAGCGACTGCTGGCTTTGT 1750 chr18 58335325 58335343 +/− 19AGCGACTGCTGGCTTTGTC 1751 chr18 58335326 58335344 +/− 19GCGACTGCTGGCTTTGTCT 1752 chr18 58335327 58335345 +/− 19CGACTGCTGGCTTTGTCTG 1753 chr18 58335328 58335346 +/− 19GACTGCTGGCTTTGTCTGG 1754 chr18 58335329 58335347 +/− 19ACTGCTGGCTTTGTCTGGA 1755 chr18 58335330 58335348 +/− 19CTGCTGGCTTTGTCTGGAT 1756 chr18 58335331 58335349 +/− 19TGCTGGCTTTGTCTGGATA 1757 chr18 58335332 58335350 +/− 19GCTGGCTTTGTCTGGATAG 1758 chr18 58335333 58335351 +/− 19CTGGCTTTGTCTGGATAGG 1759 chr18 58335334 58335352 +/− 19TGGCTTTGTCTGGATAGGG 1760 chr18 58335335 58335353 +/− 19GGCTTTGTCTGGATAGGGT 1761 chr18 58335336 58335354 +/− 19GCTTTGTCTGGATAGGGTG 1762 chr18 58335337 58335355 +/− 19CTTTGTCTGGATAGGGTGG 1763 chr18 58335338 58335356 +/− 19TTTGTCTGGATAGGGTGGG 1764 chr18 58335339 58335357 +/− 19TTGTCTGGATAGGGTGGGT 1765 chr18 58335340 58335358 +/− 19TGTCTGGATAGGGTGGGTT 1766 chr18 58335341 58335359 +/− 19GTCTGGATAGGGTGGGTTT 1767 chr18 58335342 58335360 +/− 19TCTGGATAGGGTGGGTTTC 1768 chr18 58335343 58335361 +/− 19CTGGATAGGGTGGGTTTCA 1769 chr18 58335344 58335362 +/− 19TGGATAGGGTGGGTTTCAG 1770 chr18 58335345 58335363 +/− 19GGATAGGGTGGGTTTCAGG 1771 chr18 58335346 58335364 +/− 19GATAGGGTGGGTTTCAGGG 1772 chr18 58335347 58335365 +/− 19ATAGGGTGGGTTTCAGGGA 1773 chr18 58335348 58335366 +/− 19TAGGGTGGGTTTCAGGGAT 1774 chr18 58335349 58335367 +/− 19AGGGTGGGTTTCAGGGATT 1775 chr18 58335350 58335368 +/− 19GGGTGGGTTTCAGGGATTC 1776 chr18 58335351 58335369 +/− 19GGTGGGTTTCAGGGATTCT 1777 chr18 58335352 58335370 +/− 19GTGGGTTTCAGGGATTCTG 1778 chr18 58335353 58335371 +/− 19TGGGTTTCAGGGATTCTGA 1779 chr18 58335354 58335372 +/− 19GGGTTTCAGGGATTCTGAT 1780 chr18 58335355 58335373 +/− 19GGTTTCAGGGATTCTGATC 1781 chr18 58335356 58335374 +/− 19GTTTCAGGGATTCTGATCT 1782 chr18 58335357 58335375 +/− 19TTTCAGGGATTCTGATCTC 1783 chr18 58335358 58335376 +/− 19TTCAGGGATTCTGATCTCA 1784 chr18 58335359 58335377 +/− 19TCAGGGATTCTGATCTCAC 1785 chr18 58335360 58335378 +/− 19CAGGGATTCTGATCTCACG 1786 chr18 58335361 58335379 +/− 19AGGGATTCTGATCTCACGT 1787 chr18 58335362 58335380 +/− 19GGGATTCTGATCTCACGTC 1788 chr18 58335363 58335381 +/− 19GGATTCTGATCTCACGTCA 1789 chr18 58335364 58335382 +/− 19GATTCTGATCTCACGTCAC 1790 chr18 58335365 58335383 +/− 19ATTCTGATCTCACGTCACC 1791 chr18 58335366 58335384 +/− 19TTCTGATCTCACGTCACCT 1792 chr18 58335367 58335385 +/− 19TCTGATCTCACGTCACCTG 1793 chr18 58335368 58335386 +/− 19CTGATCTCACGTCACCTGC 1794 chr18 58335369 58335387 +/− 19TGATCTCACGTCACCTGCC 1795 chr18 58335370 58335388 +/− 19GATCTCACGTCACCTGCCT 1796 chr18 58335371 58335389 +/− 19ATCTCACGTCACCTGCCTT 1797 chr18 58335372 58335390 +/− 19TCTCACGTCACCTGCCTTA 1798 chr18 58335373 58335391 +/− 19CTCACGTCACCTGCCTTAC 1799 chr18 58335374 58335392 +/− 19TCACGTCACCTGCCTTACA 1800 chr18 58335375 58335393 +/− 19CACGTCACCTGCCTTACAG 1801 chr18 58335376 58335394 +/− 19ACGTCACCTGCCTTACAGC 1802 chr18 58335377 58335395 +/− 19CGTCACCTGCCTTACAGCG 1803 chr18 58335378 58335396 +/− 19GTCACCTGCCTTACAGCGC 1804 chr18 58335379 58335397 +/− 19TCACCTGCCTTACAGCGCT 1805 chr18 58335380 58335398 +/− 19CACCTGCCTTACAGCGCTG 1806 chr18 58335381 58335399 +/− 19ACCTGCCTTACAGCGCTGC 1807 chr18 58335382 58335400 +/− 19CCTGCCTTACAGCGCTGCC 1808 chr18 58335383 58335401 +/− 19CTGCCTTACAGCGCTGCCA 1809 chr18 58335384 58335402 +/− 19TGCCTTACAGCGCTGCCAC 1810 chr18 58335385 58335403 +/− 19GCCTTACAGCGCTGCCACA 1811 chr18 58335386 58335404 +/− 19CCTTACAGCGCTGCCACAG 1812 chr18 58335387 58335405 +/− 19CTTACAGCGCTGCCACAGC 1813 chr18 58335388 58335406 +/− 19TTACAGCGCTGCCACAGCA 1814 chr18 58335389 58335407 +/− 19TACAGCGCTGCCACAGCAG 1815 chr18 58335390 58335408 +/− 19ACAGCGCTGCCACAGCAGT 1816 chr18 58335391 58335409 +/− 19CAGCGCTGCCACAGCAGTG 1817 chr18 58335392 58335410 +/− 19AGCGCTGCCACAGCAGTGG 1818 chr18 58335393 58335411 +/− 19GCGCTGCCACAGCAGTGGG 1819 chr18 58335394 58335412 +/− 19CGCTGCCACAGCAGTGGGC 1820 chr18 58335395 58335413 +/− 19GCTGCCACAGCAGTGGGCC 1821 chr18 58335396 58335414 +/− 19CTGCCACAGCAGTGGGCCC 1822 chr18 58335397 58335415 +/− 19TGCCACAGCAGTGGGCCCT 1823 chr18 58335398 58335416 +/− 19GCCACAGCAGTGGGCCCTG 1824 chr18 58335399 58335417 +/− 19CCACAGCAGTGGGCCCTGA 1825 chr18 58335400 58335418 +/− 19CACAGCAGTGGGCCCTGAT 1826 chr18 58335401 58335419 +/− 19ACAGCAGTGGGCCCTGATT 1827 chr18 58335402 58335420 +/− 19CAGCAGTGGGCCCTGATTC 1828 chr18 58335403 58335421 +/− 19AGCAGTGGGCCCTGATTCA 1829 chr18 58335404 58335422 +/− 19GCAGTGGGCCCTGATTCAG 1830 chr18 58335405 58335423 +/− 19CAGTGGGCCCTGATTCAGA 1831 chr18 58335406 58335424 +/− 19AGTGGGCCCTGATTCAGAC 1832 chr18 58335407 58335425 +/− 19GTGGGCCCTGATTCAGACA 1833 chr18 58335408 58335426 +/− 19TGGGCCCTGATTCAGACAG 1834 chr18 58335409 58335427 +/− 19GGGCCCTGATTCAGACAGC 1835 chr18 58335410 58335428 +/− 19GGCCCTGATTCAGACAGCA 1836 chr18 58335411 58335429 +/− 19GCCCTGATTCAGACAGCAG 1837 chr18 58335412 58335430 +/− 19CCCTGATTCAGACAGCAGG 1838 chr18 58335317 58335335 +/− 19TGGTCATCAGCGACTGCTG 1839 chr18 58335413 58335431 +/− 19CCTGATTCAGACAGCAGGG 1840 chr18 58335414 58335432 +/− 19CTGATTCAGACAGCAGGGG 1841 chr18 58335415 58335433 +/− 19TGATTCAGACAGCAGGGGG 1842 chr18 58335416 58335434 +/− 19GATTCAGACAGCAGGGGGT 1843 chr18 58335417 58335435 +/− 19ATTCAGACAGCAGGGGGTC 1844 chr18 58335418 58335436 +/− 19TTCAGACAGCAGGGGGTCA 1845 chr18 58335419 58335437 +/− 19TCAGACAGCAGGGGGTCAT 1846 chr18 58335420 58335438 +/− 19CAGACAGCAGGGGGTCATC 1847 chr18 58335421 58335439 +/− 19AGACAGCAGGGGGTCATCC 1848 chr18 58335422 58335440 +/− 19GACAGCAGGGGGTCATCCC 1849 chr18 58335423 58335441 +/− 19ACAGCAGGGGGTCATCCCC 1850 chr18 58335424 58335442 +/− 19CAGCAGGGGGTCATCCCCT 1851 chr18 58335425 58335443 +/− 19AGCAGGGGGTCATCCCCTA 1852 chr18 58335426 58335444 +/− 19GCAGGGGGTCATCCCCTAA 1853 chr18 58335427 58335445 +/− 19CAGGGGGTCATCCCCTAAG 1854 chr18 58335428 58335446 +/− 19AGGGGGTCATCCCCTAAGT 1855 chr18 58335429 58335447 +/− 19GGGGGTCATCCCCTAAGTG 1856

TABLE 13 20-mer target-specific ASOs SEQ ID CHR START END STRAND KmerSEQUENCE NO: chr18 58335318 58335337 +/− 20 GGTCATCAGCGACTGCTGGC 1857chr18 58335319 58335338 +/− 20 GTCATCAGCGACTGCTGGCT 1858 chr18 5833532058335339 +/− 20 TCATCAGCGACTGCTGGCTT 1859 chr18 58335321 58335340 +/− 20CATCAGCGACTGCTGGCTTT 1860 chr18 58335322 58335341 +/− 20ATCAGCGACTGCTGGCTTTG 1861 chr18 58335323 58335342 +/− 20TCAGCGACTGCTGGCTTTGT 1862 chr18 58335324 58335343 +/− 20CAGCGACTGCTGGCTTTGTC 1863 chr18 58335325 58335344 +/− 20AGCGACTGCTGGCTTTGTCT 1864 chr18 58335326 58335345 +/− 20GCGACTGCTGGCTTTGTCTG 1865 chr18 58335327 58335346 +/− 20CGACTGCTGGCTTTGTCTGG 1866 chr18 58335328 58335347 +/− 20GACTGCTGGCTTTGTCTGGA 1867 chr18 58335329 58335348 +/− 20ACTGCTGGCTTTGTCTGGAT 1868 chr18 58335330 58335349 +/− 20CTGCTGGCTTTGTCTGGATA 1869 chr18 58335331 58335350 +/− 20TGCTGGCTTTGTCTGGATAG 1870 chr18 58335332 58335351 +/− 20GCTGGCTTTGTCTGGATAGG 3 chr18 58335333 58335352 +/− 20CTGGCTTTGTCTGGATAGGG 1871 chr18 58335334 58335353 +/− 20TGGCTTTGTCTGGATAGGGT 1872 chr18 58335335 58335354 +/− 20GGCTTTGTCTGGATAGGGTG 1873 chr18 58335336 58335355 +/− 20GCTTTGTCTGGATAGGGTGG 1874 chr18 58335337 58335356 +/− 20CTTTGTCTGGATAGGGTGGG 1875 chr18 58335338 58335357 +/− 20TTTGTCTGGATAGGGTGGGT 1876 chr18 58335339 58335358 +/− 20TTGTCTGGATAGGGTGGGTT 1877 chr18 58335340 58335359 +/− 20TGTCTGGATAGGGTGGGTTT 1878 chr18 58335341 58335360 +/− 20GTCTGGATAGGGTGGGTTTC 1879 chr18 58335342 58335361 +/− 20TCTGGATAGGGTGGGTTTCA 1880 chr18 58335343 58335362 +/− 20CTGGATAGGGTGGGTTTCAG 1881 chr18 58335344 58335363 +/− 20TGGATAGGGTGGGTTTCAGG 1882 chr18 58335345 58335364 +/− 20GGATAGGGTGGGTTTCAGGG 1883 chr18 58335346 58335365 +/− 20GATAGGGTGGGTTTCAGGGA 1884 chr18 58335347 58335366 +/− 20ATAGGGTGGGTTTCAGGGAT 1885 chr18 58335348 58335367 +/− 20TAGGGTGGGTTTCAGGGATT 1886 chr18 58335349 58335368 +/− 20AGGGTGGGTTTCAGGGATTC 1887 chr18 58335350 58335369 +/− 20GGGTGGGTTTCAGGGATTCT 1888 chr18 58335351 58335370 +/− 20GGTGGGTTTCAGGGATTCTG 1889 chr18 58335352 58335371 +/− 20GTGGGTTTCAGGGATTCTGA 1 chr18 58335353 58335372 +/− 20TGGGTTTCAGGGATTCTGAT 1890 chr18 58335354 58335373 +/− 20GGGTTTCAGGGATTCTGATC 1891 chr18 58335355 58335374 +/− 20GGTTTCAGGGATTCTGATCT 1892 chr18 58335356 58335375 +/− 20GTTTCAGGGATTCTGATCTC 1893 chr18 58335357 58335376 +/− 20TTTCAGGGATTCTGATCTCA 1894 chr18 58335358 58335377 +/− 20TTCAGGGATTCTGATCTCAC 1895 chr18 58335359 58335378 +/− 20TCAGGGATTCTGATCTCACG 1896 chr18 58335360 58335379 +/− 20CAGGGATTCTGATCTCACGT 1897 chr18 58335361 58335380 +/− 20AGGGATTCTGATCTCACGTC 1898 chr18 58335362 58335381 +/− 20GGGATTCTGATCTCACGTCA 1899 chr18 58335363 58335382 +/− 20GGATTCTGATCTCACGTCAC 1900 chr18 58335364 58335383 +/− 20GATTCTGATCTCACGTCACC 1901 chr18 58335365 58335384 +/− 20ATTCTGATCTCACGTCACCT 1902 chr18 58335366 58335385 +/− 20TTCTGATCTCACGTCACCTG 1903 chr18 58335367 58335386 +/− 20TCTGATCTCACGTCACCTGC 1904 chr18 58335368 58335387 +/− 20CTGATCTCACGTCACCTGCC 1905 chr18 58335369 58335388 +/− 20TGATCTCACGTCACCTGCCT 1906 chr18 58335370 58335389 +/− 20GATCTCACGTCACCTGCCTT 1907 chr18 58335371 58335390 +/− 20ATCTCACGTCACCTGCCTTA 1908 chr18 58335372 58335391 +/− 20TCTCACGTCACCTGCCTTAC 4 chr18 58335373 58335392 +/− 20CTCACGTCACCTGCCTTACA 1909 chr18 58335374 58335393 +/− 20TCACGTCACCTGCCTTACAG 1910 chr18 58335375 58335394 +/− 20CACGTCACCTGCCTTACAGC 1911 chr18 58335376 58335395 +/− 20ACGTCACCTGCCTTACAGCG 1912 chr18 58335377 58335396 +/− 20CGTCACCTGCCTTACAGCGC 1913 chr18 58335378 58335397 +/− 20GTCACCTGCCTTACAGCGCT 1914 chr18 58335379 58335398 +/− 20TCACCTGCCTTACAGCGCTG 1915 chr18 58335380 58335399 +/− 20CACCTGCCTTACAGCGCTGC 1916 chr18 58335381 58335400 +/− 20ACCTGCCTTACAGCGCTGCC 1917 chr18 58335382 58335401 +/− 20CCTGCCTTACAGCGCTGCCA 1918 chr18 58335383 58335402 +/− 20CTGCCTTACAGCGCTGCCAC 1919 chr18 58335384 58335403 +/− 20TGCCTTACAGCGCTGCCACA 1920 chr18 58335385 58335404 +/− 20GCCTTACAGCGCTGCCACAG 1921 chr18 58335386 58335405 +/− 20CCTTACAGCGCTGCCACAGC 1922 chr18 58335387 58335406 +/− 20CTTACAGCGCTGCCACAGCA 1923 chr18 58335388 58335407 +/− 20TTACAGCGCTGCCACAGCAG 1924 chr18 58335389 58335408 +/− 20TACAGCGCTGCCACAGCAGT 1925 chr18 58335390 58335409 +/− 20ACAGCGCTGCCACAGCAGTG 1926 chr18 58335391 58335410 +/− 20CAGCGCTGCCACAGCAGTGG 1927 chr18 58335392 58335411 +/− 20AGCGCTGCCACAGCAGTGGG 5 chr18 58335393 58335412 +/− 20GCGCTGCCACAGCAGTGGGC 1928 chr18 58335394 58335413 +/− 20CGCTGCCACAGCAGTGGGCC 1929 chr18 58335395 58335414 +/− 20GCTGCCACAGCAGTGGGCCC 1930 chr18 58335396 58335415 +/− 20CTGCCACAGCAGTGGGCCCT 1931 chr18 58335397 58335416 +/− 20TGCCACAGCAGTGGGCCCTG 1932 chr18 58335398 58335417 +/− 20GCCACAGCAGTGGGCCCTGA 1933 chr18 58335399 58335418 +/− 20CCACAGCAGTGGGCCCTGAT 1934 chr18 58335400 58335419 +/− 20CACAGCAGTGGGCCCTGATT 1935 chr18 58335401 58335420 +/− 20ACAGCAGTGGGCCCTGATTC 1936 chr18 58335402 58335421 +/− 20CAGCAGTGGGCCCTGATTCA 1937 chr18 58335403 58335422 +/− 20AGCAGTGGGCCCTGATTCAG 1938 chr18 58335404 58335423 +/− 20GCAGTGGGCCCTGATTCAGA 1939 chr18 58335405 58335424 +/− 20CAGTGGGCCCTGATTCAGAC 1940 chr18 58335406 58335425 +/− 20AGTGGGCCCTGATTCAGACA 1941 chr18 58335407 58335426 +/− 20GTGGGCCCTGATTCAGACAG 1942 chr18 58335408 58335427 +/− 20TGGGCCCTGATTCAGACAGC 1943 chr18 58335409 58335428 +/− 20GGGCCCTGATTCAGACAGCA 1944 chr18 58335410 58335429 +/− 20GGCCCTGATTCAGACAGCAG 1945 chr18 58335411 58335430 +/− 20GCCCTGATTCAGACAGCAGG 1946 chr18 58335317 58335336 +/− 20TGGTCATCAGCGACTGCTGG 1947 chr18 58335412 58335431 +/− 20CCCTGATTCAGACAGCAGGG 2 chr18 58335413 58335432 +/− 20CCTGATTCAGACAGCAGGGG 1948 chr18 58335414 58335433 +/− 20CTGATTCAGACAGCAGGGGG 1949 chr18 58335415 58335434 +/− 20TGATTCAGACAGCAGGGGGT 1950 chr18 58335416 58335435 +/− 20GATTCAGACAGCAGGGGGTC 1951 chr18 58335417 58335436 +/− 20ATTCAGACAGCAGGGGGTCA 1952 chr18 58335418 58335437 +/− 20TTCAGACAGCAGGGGGTCAT 1953 chr18 58335419 58335438 +/− 20TCAGACAGCAGGGGGTCATC 1954 chr18 58335420 58335439 +/− 20CAGACAGCAGGGGGTCATCC 1955 chr18 58335421 58335440 +/− 20AGACAGCAGGGGGTCATCCC 1956 chr18 58335422 58335441 +/− 20GACAGCAGGGGGTCATCCCC 1957 chr18 58335423 58335442 +/− 20ACAGCAGGGGGTCATCCCCT 1958 chr18 58335424 58335443 +/− 20CAGCAGGGGGTCATCCCCTA 1959 chr18 58335425 58335444 +/− 20AGCAGGGGGTCATCCCCTAA 1960 chr18 58335426 58335445 +/− 20GCAGGGGGTCATCCCCTAAG 1961 chr18 58335427 58335446 +/− 20CAGGGGGTCATCCCCTAAGT 1962 chr18 58335428 58335447 +/− 20AGGGGGTCATCCCCTAAGTG 1963

TABLE 14 21-mer target-specific ASOs SEQ ID CHR START END STRAND KmerSEQUENCE NO: chr18 58335318 58335338 +/− 21 GGTCATCAGCGACTGCTGGCT 1964chr18 58335319 58335339 +/− 21 GTCATCAGCGACTGCTGGCTT 1965 chr18 5833532058335340 +/− 21 TCATCAGCGACTGCTGGCTTT 1966 chr18 58335321 58335341 +/−21 CATCAGCGACTGCTGGCTTTG 1967 chr18 58335322 58335342 +/− 21ATCAGCGACTGCTGGCTTTGT 1968 chr18 58335323 58335343 +/− 21TCAGCGACTGCTGGCTTTGTC 1969 chr18 58335324 58335344 +/− 21CAGCGACTGCTGGCTTTGTCT 1970 chr18 58335325 58335345 +/− 21AGCGACTGCTGGCTTTGTCTG 1971 chr18 58335326 58335346 +/− 21GCGACTGCTGGCTTTGTCTGG 1972 chr18 58335327 58335347 +/− 21CGACTGCTGGCTTTGTCTGGA 1973 chr18 58335328 58335348 +/− 21GACTGCTGGCTTTGTCTGGAT 1974 chr18 58335329 58335349 +/− 21ACTGCTGGCTTTGTCTGGATA 1975 chr18 58335330 58335350 +/− 21CTGCTGGCTTTGTCTGGATAG 1976 chr18 58335331 58335351 +/− 21TGCTGGCTTTGTCTGGATAGG 1977 chr18 58335332 58335352 +/− 21GCTGGCTTTGTCTGGATAGGG 1978 chr18 58335333 58335353 +/− 21CTGGCTTTGTCTGGATAGGGT 1979 chr18 58335334 58335354 +/− 21TGGCTTTGTCTGGATAGGGTG 1980 chr18 58335335 58335355 +/− 21GGCTTTGTCTGGATAGGGTGG 1981 chr18 58335336 58335356 +/− 21GCTTTGTCTGGATAGGGTGGG 1982 chr18 58335337 58335357 +/− 21CTTTGTCTGGATAGGGTGGGT 1983 chr18 58335338 58335358 +/− 21TTTGTCTGGATAGGGTGGGTT 1984 chr18 58335339 58335359 +/− 21TTGTCTGGATAGGGTGGGTTT 1985 chr18 58335340 58335360 +/− 21TGTCTGGATAGGGTGGGTTTC 1986 chr18 58335341 58335361 +/− 21GTCTGGATAGGGTGGGTTTCA 1987 chr18 58335342 58335362 +/− 21TCTGGATAGGGTGGGTTTCAG 1988 chr18 58335343 58335363 +/− 21CTGGATAGGGTGGGTTTCAGG 1989 chr18 58335344 58335364 +/− 21TGGATAGGGTGGGTTTCAGGG 1990 chr18 58335345 58335365 +/− 21GGATAGGGTGGGTTTCAGGGA 1991 chr18 58335346 58335366 +/− 21GATAGGGTGGGTTTCAGGGAT 1992 chr18 58335347 58335367 +/− 21ATAGGGTGGGTTTCAGGGATT 1993 chr18 58335348 58335368 +/− 21TAGGGTGGGTTTCAGGGATTC 1994 chr18 58335349 58335369 +/− 21AGGGTGGGTTTCAGGGATTCT 1995 chr18 58335350 58335370 +/− 21GGGTGGGTTTCAGGGATTCTG 1996 chr18 58335351 58335371 +/− 21GGTGGGTTTCAGGGATTCTGA 1997 chr18 58335352 58335372 +/− 21GTGGGTTTCAGGGATTCTGAT 1998 chr18 58335353 58335373 +/− 21TGGGTTTCAGGGATTCTGATC 1999 chr18 58335354 58335374 +/− 21GGGTTTCAGGGATTCTGATCT 2000 chr18 58335355 58335375 +/− 21GGTTTCAGGGATTCTGATCTC 2001 chr18 58335356 58335376 +/− 21GTTTCAGGGATTCTGATCTCA 2002 chr18 58335357 58335377 +/− 21TTTCAGGGATTCTGATCTCAC 2003 chr18 58335358 58335378 +/− 21TTCAGGGATTCTGATCTCACG 2004 chr18 58335359 58335379 +/− 21TCAGGGATTCTGATCTCACGT 2005 chr18 58335360 58335380 +/− 21CAGGGATTCTGATCTCACGTC 2006 chr18 58335361 58335381 +/− 21AGGGATTCTGATCTCACGTCA 2007 chr18 58335362 58335382 +/− 21GGGATTCTGATCTCACGTCAC 2008 chr18 58335363 58335383 +/− 21GGATTCTGATCTCACGTCACC 2009 chr18 58335364 58335384 +/− 21GATTCTGATCTCACGTCACCT 2010 chr18 58335365 58335385 +/− 21ATTCTGATCTCACGTCACCTG 2011 chr18 58335366 58335386 +/− 21TTCTGATCTCACGTCACCTGC 2012 chr18 58335367 58335387 +/− 21TCTGATCTCACGTCACCTGCC 2013 chr18 58335368 58335388 +/− 21CTGATCTCACGTCACCTGCCT 2014 chr18 58335369 58335389 +/− 21TGATCTCACGTCACCTGCCTT 2015 chr18 58335370 58335390 +/− 21GATCTCACGTCACCTGCCTTA 2016 chr18 58335371 58335391 +/− 21ATCTCACGTCACCTGCCTTAC 2017 chr18 58335372 58335392 +/− 21TCTCACGTCACCTGCCTTACA 2018 chr18 58335373 58335393 +/− 21CTCACGTCACCTGCCTTACAG 2019 chr18 58335374 58335394 +/− 21TCACGTCACCTGCCTTACAGC 2020 chr18 58335375 58335395 +/− 21CACGTCACCTGCCTTACAGCG 2021 chr18 58335376 58335396 +/− 21ACGTCACCTGCCTTACAGCGC 2022 chr18 58335377 58335397 +/− 21CGTCACCTGCCTTACAGCGCT 2023 chr18 58335378 58335398 +/− 21GTCACCTGCCTTACAGCGCTG 2024 chr18 58335379 58335399 +/− 21TCACCTGCCTTACAGCGCTGC 2025 chr18 58335380 58335400 +/− 21CACCTGCCTTACAGCGCTGCC 2026 chr18 58335381 58335401 +/− 21ACCTGCCTTACAGCGCTGCCA 2027 chr18 58335382 58335402 +/− 21CCTGCCTTACAGCGCTGCCAC 2028 chr18 58335383 58335403 +/− 21CTGCCTTACAGCGCTGCCACA 2029 chr18 58335384 58335404 +/− 21TGCCTTACAGCGCTGCCACAG 2030 chr18 58335385 58335405 +/− 21GCCTTACAGCGCTGCCACAGC 2031 chr18 58335386 58335406 +/− 21CCTTACAGCGCTGCCACAGCA 2032 chr18 58335387 58335407 +/− 21CTTACAGCGCTGCCACAGCAG 2033 chr18 58335388 58335408 +/− 21TTACAGCGCTGCCACAGCAGT 2034 chr18 58335389 58335409 +/− 21TACAGCGCTGCCACAGCAGTG 2035 chr18 58335390 58335410 +/− 21ACAGCGCTGCCACAGCAGTGG 2036 chr18 58335391 58335411 +/− 21CAGCGCTGCCACAGCAGTGGG 2037 chr18 58335392 58335412 +/− 21AGCGCTGCCACAGCAGTGGGC 2038 chr18 58335393 58335413 +/− 21GCGCTGCCACAGCAGTGGGCC 2039 chr18 58335394 58335414 +/− 21CGCTGCCACAGCAGTGGGCCC 2040 chr18 58335395 58335415 +/− 21GCTGCCACAGCAGTGGGCCCT 2041 chr18 58335396 58335416 +/− 21CTGCCACAGCAGTGGGCCCTG 2042 chr18 58335397 58335417 +/− 21TGCCACAGCAGTGGGCCCTGA 2043 chr18 58335398 58335418 +/− 21GCCACAGCAGTGGGCCCTGAT 2044 chr18 58335399 58335419 +/− 21CCACAGCAGTGGGCCCTGATT 2045 chr18 58335400 58335420 +/− 21CACAGCAGTGGGCCCTGATTC 2046 chr18 58335401 58335421 +/− 21ACAGCAGTGGGCCCTGATTCA 2047 chr18 58335402 58335422 +/− 21CAGCAGTGGGCCCTGATTCAG 2048 chr18 58335403 58335423 +/− 21AGCAGTGGGCCCTGATTCAGA 2049 chr18 58335404 58335424 +/− 21GCAGTGGGCCCTGATTCAGAC 2050 chr18 58335405 58335425 +/− 21CAGTGGGCCCTGATTCAGACA 2051 chr18 58335406 58335426 +/− 21AGTGGGCCCTGATTCAGACAG 2052 chr18 58335407 58335427 +/− 21GTGGGCCCTGATTCAGACAGC 2053 chr18 58335408 58335428 +/−  21TGGGCCCTGATTCAGACAGCA 2054 chr18 58335409 58335429 +/− 21GGGCCCTGATTCAGACAGCAG 2055 chr18 58335410 58335430 +/− 21GGCCCTGATTCAGACAGCAGG 2056 chr18 58335317 58335337 +/− 21TGGTCATCAGCGACTGCTGGC 2057 chr18 58335411 58335431 +/− 21GCCCTGATTCAGACAGCAGGG 2058 chr18 58335412 58335432 +/− 21CCCTGATTCAGACAGCAGGGG 2059 chr18 58335413 58335433 +/− 21CCTGATTCAGACAGCAGGGGG 2060 chr18 58335414 58335434 +/− 21CTGATTCAGACAGCAGGGGGT 2061 chr18 58335415 58335435 +/− 21TGATTCAGACAGCAGGGGGTC 2062 chr18 58335416 58335436 +/− 21GATTCAGACAGCAGGGGGTCA 2063 chr18 58335417 58335437 +/− 21ATTCAGACAGCAGGGGGTCAT 2064 chr18 58335418 58335438 +/− 21TTCAGACAGCAGGGGGTCATC 2065 chr18 58335419 58335439 +/− 21TCAGACAGCAGGGGGTCATCC 2066 chr18 58335420 58335440 +/− 21CAGACAGCAGGGGGTCATCCC 2067 chr18 58335421 58335441 +/− 21AGACAGCAGGGGGTCATCCCC 2068 chr18 58335422 58335442 +/− 21GACAGCAGGGGGTCATCCCCT 2069 chr18 58335423 58335443 +/− 21ACAGCAGGGGGTCATCCCCTA 2070 chr18 58335424 58335444 +/− 21CAGCAGGGGGTCATCCCCTAA 2071 chr18 58335425 58335445 +/− 21AGCAGGGGGTCATCCCCTAAG 2072 chr18 58335426 58335446 +/− 21GCAGGGGGTCATCCCCTAAGT 2073 chr18 58335427 58335447 +/− 21CAGGGGGTCATCCCCTAAGTG 2074

TABLE 15 22-mer target-specific ASOs SEQ ID CHR START END STRAND KmerSEQUENCE NO: chr18 58335318 58335339 +/− 22 GGTCATCAGCGACTGCTGGCTT 2075chr18 58335319 58335340 +/− 22 GTCATCAGCGACTGCTGGCTTT 2076 chr1858335320 58335341 +/− 22 TCATCAGCGACTGCTGGCTTTG 2077 chr18 5833532158335342 +/− 22 CATCAGCGACTGCTGGCTTTGT 2078 chr18 58335322 58335343 +/−22 ATCAGCGACTGCTGGCTTTGTC 2079 chr18 58335323 58335344 +/− 22TCAGCGACTGCTGGCTTTGTCT 2080 chr18 58335324 58335345 +/− 22CAGCGACTGCTGGCTTTGTCTG 2081 chr18 58335325 58335346 +/− 22AGCGACTGCTGGCTTTGTCTGG 2082 chr18 58335326 58335347 +/− 22GCGACTGCTGGCTTTGTCTGGA 2083 chr18 58335327 58335348 +/− 22CGACTGCTGGCTTTGTCTGGAT 2084 chr18 58335328 58335349 +/− 22GACTGCTGGCTTTGTCTGGATA 2085 chr18 58335329 58335350 +/− 22ACTGCTGGCTTTGTCTGGATAG 2086 chr18 58335330 58335351 +/− 22CTGCTGGCTTTGTCTGGATAGG 2087 chr18 58335331 58335352 +/− 22TGCTGGCTTTGTCTGGATAGGG 2088 chr18 58335332 58335353 +/− 22GCTGGCTTTGTCTGGATAGGGT 2089 chr18 58335333 58335354 +/− 22CTGGCTTTGTCTGGATAGGGTG 2090 chr18 58335334 58335355 +/− 22TGGCTTTGTCTGGATAGGGTGG 2091 chr18 58335335 58335356 +/− 22GGCTTTGTCTGGATAGGGTGGG 2092 chr18 58335336 58335357 +/− 22GCTTTGTCTGGATAGGGTGGGT 2093 chr18 58335337 58335358 +/− 22CTTTGTCTGGATAGGGTGGGTT 2094 chr18 58335338 58335359 +/− 22TTTGTCTGGATAGGGTGGGTTT 2095 chr18 58335339 58335360 +/− 22TTGTCTGGATAGGGTGGGTTTC 2096 chr18 58335340 58335361 +/− 22TGTCTGGATAGGGTGGGTTTCA 2097 chr18 58335341 58335362 +/− 22GTCTGGATAGGGTGGGTTTCAG 2098 chr18 58335342 58335363 +/− 22TCTGGATAGGGTGGGTTTCAGG 2099 chr18 58335343 58335364 +/− 22CTGGATAGGGTGGGTTTCAGGG 2100 chr18 58335344 58335365 +/− 22TGGATAGGGTGGGTTTCAGGGA 2101 chr18 58335345 58335366 +/− 22GGATAGGGTGGGTTTCAGGGAT 2102 chr18 58335346 58335367 +/− 22GATAGGGTGGGTTTCAGGGATT 2103 chr18 58335347 58335368 +/− 22ATAGGGTGGGTTTCAGGGATTC 2104 chr18 58335348 58335369 +/− 22TAGGGTGGGTTTCAGGGATTCT 2105 chr18 58335349 58335370 +/− 22AGGGTGGGTTTCAGGGATTCTG 2106 chr18 58335350 58335371 +/− 22GGGTGGGTTTCAGGGATTCTGA 2107 chr18 58335351 58335372 +/− 22GGTGGGTTTCAGGGATTCTGAT 2108 chr18 58335352 58335373 +/− 22GTGGGTTTCAGGGATTCTGATC 2109 chr18 58335353 58335374 +/− 22TGGGTTTCAGGGATTCTGATCT 2110 chr18 58335354 58335375 +/− 22GGGTTTCAGGGATTCTGATCTC 2111 chr18 58335355 58335376 +/− 22GGTTTCAGGGATTCTGATCTCA 2112 chr18 58335356 58335377 +/− 22GTTTCAGGGATTCTGATCTCAC 2113 chr18 58335357 58335378 +/− 22TTTCAGGGATTCTGATCTCACG 2114 chr18 58335358 58335379 +/− 22TTCAGGGATTCTGATCTCACGT 2115 chr18 58335359 58335380 +/− 22TCAGGGATTCTGATCTCACGTC 2116 chr18 58335360 58335381 +/− 22CAGGGATTCTGATCTCACGTCA 2117 chr18 58335361 58335382 +/− 22AGGGATTCTGATCTCACGTCAC 2118 chr18 58335362 58335383 +/− 22GGGATTCTGATCTCACGTCACC 2119 chr18 58335363 58335384 +/− 22GGATTCTGATCTCACGTCACCT 2120 chr18 58335364 58335385 +/− 22GATTCTGATCTCACGTCACCTG 2121 chr18 58335365 58335386 +/− 22ATTCTGATCTCACGTCACCTGC 2122 chr18 58335366 58335387 +/− 22TTCTGATCTCACGTCACCTGCC 2123 chr18 58335367 58335388 +/− 22TCTGATCTCACGTCACCTGCCT 2124 chr18 58335368 58335389 +/− 22CTGATCTCACGTCACCTGCCTT 2125 chr18 58335369 58335390 +/− 22TGATCTCACGTCACCTGCCTTA 2126 chr18 58335370 58335391 +/− 22GATCTCACGTCACCTGCCTTAC 2127 chr18 58335371 58335392 +/− 22ATCTCACGTCACCTGCCTTACA 2128 chr18 58335372 58335393 +/− 22TCTCACGTCACCTGCCTTACAG 2129 chr18 58335373 58335394 +/− 22CTCACGTCACCTGCCTTACAGC 2130 chr18 58335374 58335395 +/− 22TCACGTCACCTGCCTTACAGCG 2131 chr18 58335375 58335396 +/− 22CACGTCACCTGCCTTACAGCGC 2132 chr18 58335376 58335397 +/− 22ACGTCACCTGCCTTACAGCGCT 2133 chr18 58335377 58335398 +/− 22CGTCACCTGCCTTACAGCGCTG 2134 chr18 58335378 58335399 +/− 22GTCACCTGCCTTACAGCGCTGC 2135 chr18 58335379 58335400 +/− 22TCACCTGCCTTACAGCGCTGCC 2136 chr18 58335380 58335401 +/− 22CACCTGCCTTACAGCGCTGCCA 2137 chr18 58335381 58335402 +/− 22ACCTGCCTTACAGCGCTGCCAC 2138 chr18 58335382 58335403 +/− 22CCTGCCTTACAGCGCTGCCACA 2139 chr18 58335383 58335404 +/− 22CTGCCTTACAGCGCTGCCACAG 2140 chr18 58335384 58335405 +/− 22TGCCTTACAGCGCTGCCACAGC 2141 chr18 58335385 58335406 +/− 22GCCTTACAGCGCTGCCACAGCA 2142 chr18 58335386 58335407 +/− 22CCTTACAGCGCTGCCACAGCAG 2143 chr18 58335387 58335408 +/− 22CTTACAGCGCTGCCACAGCAGT 2144 chr18 58335388 58335409 +/− 22TTACAGCGCTGCCACAGCAGTG 2145 chr18 58335389 58335410 +/− 22TACAGCGCTGCCACAGCAGTGG 2146 chr18 58335390 58335411 +/− 22ACAGCGCTGCCACAGCAGTGGG 2147 chr18 58335391 58335412 +/− 22CAGCGCTGCCACAGCAGTGGGC 2148 chr18 58335392 58335413 +/− 22AGCGCTGCCACAGCAGTGGGCC 2149 chr18 58335393 58335414 +/− 22GCGCTGCCACAGCAGTGGGCCC 2150 chr18 58335394 58335415 +/− 22CGCTGCCACAGCAGTGGGCCCT 2151 chr18 58335395 58335416 +/− 22GCTGCCACAGCAGTGGGCCCTG 2152 chr18 58335396 58335417 +/− 22CTGCCACAGCAGTGGGCCCTGA 2153 chr18 58335397 58335418 +/− 22TGCCACAGCAGTGGGCCCTGAT 2154 chr18 58335398 58335419 +/− 22GCCACAGCAGTGGGCCCTGATT 2155 chr18 58335399 58335420 +/− 22CCACAGCAGTGGGCCCTGATTC 2156 chr18 58335400 58335421 +/− 22CACAGCAGTGGGCCCTGATTCA 2157 chr18 58335401 58335422 +/− 22ACAGCAGTGGGCCCTGATTCAG 2158 chr18 58335402 58335423 +/− 22CAGCAGTGGGCCCTGATTCAGA 2159 chr18 58335403 58335424 +/− 22AGCAGTGGGCCCTGATTCAGAC 2160 chr18 58335404 58335425 +/− 22GCAGTGGGCCCTGATTCAGACA 2161 chr18 58335405 58335426 +/− 22CAGTGGGCCCTGATTCAGACAG 2162 chr18 58335406 58335427 +/− 22AGTGGGCCCTGATTCAGACAGC 2163 chr18 58335407 58335428 +/− 22GTGGGCCCTGATTCAGACAGCA 2164 chr18 58335408 58335429 +/− 22TGGGCCCTGATTCAGACAGCAG 2165 chr18 58335409 58335430 +/− 22GGGCCCTGATTCAGACAGCAGG 2166 chr18 58335317 58335338 +/− 22TGGTCATCAGCGACTGCTGGCT 2167 chr18 58335410 58335431 +/− 22GGCCCTGATTCAGACAGCAGGG 2168 chr18 58335411 58335432 +/− 22GCCCTGATTCAGACAGCAGGGG 2169 chr18 58335412 58335433 +/− 22CCCTGATTCAGACAGCAGGGGG 2170 chr18 58335413 58335434 +/− 22CCTGATTCAGACAGCAGGGGGT 2171 chr18 58335414 58335435 +/− 22CTGATTCAGACAGCAGGGGGTC 2172 chr18 58335415 58335436 +/− 22TGATTCAGACAGCAGGGGGTCA 2173 chr18 58335416 58335437 +/− 22GATTCAGACAGCAGGGGGTCAT 2174 chr18 58335417 58335438 +/− 22ATTCAGACAGCAGGGGGTCATC 2175 chr18 58335418 58335439 +/− 22TTCAGACAGCAGGGGGTCATCC 2176 chr18 58335419 58335440 +/− 22TCAGACAGCAGGGGGTCATCCC 2177 chr18 58335420 58335441 +/− 22CAGACAGCAGGGGGTCATCCCC 2178 chr18 58335421 58335442 +/− 22AGACAGCAGGGGGTCATCCCCT 2179 chr18 58335422 58335443 +/− 22GACAGCAGGGGGTCATCCCCTA 2180 chr18 58335423 58335444 +/− 22ACAGCAGGGGGTCATCCCCTAA 2181 chr18 58335424 58335445 +/− 22CAGCAGGGGGTCATCCCCTAAG 2182 chr18 58335425 58335446 +/− 22AGCAGGGGGTCATCCCCTAAGT 2183 chr18 58335426 58335447 +/− 22GCAGGGGGTCATCCCCTAAGTG 2184

Also provided herein are some additional target-specific ASOs (Tables16-33) which may be used methods and/or systems of the presentdisclosure. The ASOs may be used to induce an isoform switch or modulate(e.g., inhibit or enhance) the biological activity of a specific isoformof one or several of the genes described above or elsewhere herein(e.g., genes comprising one or more of NEDD4L (ENV2), MAP3K7 (ENV3),NFYA (ENV11), ESYT2 (ENV21), MARK2 (ENV18), ST7 (ENV19), ARVCF (ENV22),SYTL2 (ENV17), R3HDM1 (ENV23), COL4A3BP (ENV9), TANGO2 (ENV6), SEPT9(ENV15), ROBO1 (ENV4), FAM122B (ENV5), CD47 (ENV13), LSR (ENV20), PBX1(ENV 16), EPB41 (ENV14), ADAM15 (ENV7),EPB41L1 (ENV8), ABI1 (ENV10),FLNB (ENV1), CTNND1 (ENV12), GPR160 (ENV24), ITGB3BP (ENV25), INCENP(ENV26), DENND1B (ENV27), CA12 (ENV28)).

As discussed above, oligonucleotide sequences comprised in a table maybe specific for a single target, or for more than one target. In somecases, oligonucleotide sequences comprised in more than one tables arespecific for a single target. For example, oligonucleotide sequencescomprised in Tables 16-33 may each be specific for a single target. Thetargets may be the same as or differ from the target(s) which theoligonucleotide sequences comprised in Tables 2-15 are specific for. Thetarget(s) may be one or more genes described above or elsewhere herein.In some cases, ASOs included in Table 16 are specific for NEDD4L (ENV2).In some cases, ASOs included in Table 17 are specific for MAP3K7 (ENV3).In some cases, ASOs included in Table 18 are specific for ROBO1 (ENV4).In some cases, ASOs included in Table 19 are specific for FAM122B(ENVS). In some cases, ASOs included in Table 20 are specific for TANGO2(ENV6). In some cases, ASOs included in Table 21 are specific for ADAM15(ENV7). In some cases, ASOs included in Table 22 are specific forEPB41L1 (ENV8). In some cases, ASOs included in Table 23 are specificfor COL4A3BP (ENV9). In some cases, ASOs included in Table 23 arespecific for ABI1 (ENV10). In some cases, ASOs included in Table 24 arespecific for NFYA (ENV11). In some cases, AS Os included in Table 26 arespecific for CTNND1 (ENV12). In some cases, ASOs included in Table 27are specific for SEPT9 (ENV15). In some cases, ASOs included in Table 28are specific for SYTL2 (ENV17). In some cases, ASOs included in Table 29are specific for MARK2 (ENV18). In some cases, ASOs included in Table 30are specific for ST7 (ENV19). In some cases, ASOs included in Table 31are specific for ESYT2 (ENV21). In some cases, ASOs included in Table 32are specific for ARVCF (ENV22). In some cases, ASOs included in Table 33are specific for R3HDM1 (ENV23).

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While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. It is not intendedthat the invention be limited by the specific examples provided withinthe specification. While the invention has been described with referenceto the aforementioned specification, the descriptions and illustrationsof the embodiments herein are not meant to be construed in a limitingsense. Numerous variations, changes, and substitutions will now occur tothose skilled in the art without departing from the invention.Furthermore, it shall be understood that all aspects of the inventionare not limited to the specific depictions, configurations or relativeproportions set forth herein which depend upon a variety of conditionsand variables. It should be understood that various alternatives to theembodiments of the invention described herein may be employed inpracticing the invention. It is therefore contemplated that theinvention shall also cover any such alternatives, modifications,variations or equivalents. It is intended that the following claimsdefine the scope of the invention and that methods and structures withinthe scope of these claims and their equivalents be covered thereby.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220112497A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1.-155. (canceled)
 156. An antisense oligonucleotide comprising asequence selected from the group consisting of: (SEQ ID NO: 1)5′-GTGGGTTTCAGGGATTCTGA-3′, (SEQ ID NO: 2) 5′-CCCTGATTCAGACAGCAGGG-3′,(SEQ ID NO: 3) 5′-GCTGGCTTTGTCTGGATAGG-3′, (SEQ ID NO: 4)5′-TCTCACGTCACCTGCCTTAC-3′, and (SEQ ID NO: 5)5′-AGCGCTGCCACAGCAGTGGG-3′,

or a complement thereof.
 157. The antisense oligonucleotide of claim156, wherein the oligonucleotide is capable of modulating splicing ofNEDD4L mRNA in a cell.
 158. The antisense oligonucleotide of claim 157,wherein the modulation of splicing comprises promoting a splicingswitch.
 159. The antisense oligonucleotide of claim 156, wherein saidoligonucleotide comprises 20-50 nucleotides.
 160. The antisenseoligonucleotide of claim 159, wherein said oligonucleotide comprises25-30 nucleotides.
 161. The antisense oligonucleotide of claim 156,wherein said oligonucleotide comprises deoxyribonucleic acid (DNA),ribonucleic acid (RNA), PNA, or a combination or hybrid thereof. 162.The antisense compound of claim 156, wherein the oligonucleotidecomprises one or more modified oligonucleotides.
 163. The antisenseoligonucleotide of claim 156, wherein the antisense oligonucleotidecomprises at least one modified internucleoside linkage.
 164. Theantisense oligonucleotide of claim 163, wherein all internucleosidelinkages are modified.
 165. The antisense oligonucleotide of claim 163,wherein the modified internucleoside linkage comprises aphosphorothioate linkage.
 166. The antisense oligonucleotide of claim156, wherein the antisense oligonucleotide comprises one or moremodified nucleoside selected from the group consisting of2′-O-methoxyethyl nucleoside, 2′-fluoro nucleoside,2′-dimethylaminooxyethoxy nucleoside, T-dimethylaminoethoxyethoxynucleoside, 2′-guanidinium nucleoside, 2′-O-guanidinium ethylnucleoside, T-carbamate nucleoside, 2′aminooxy nucleoside, T-acetamidonucleoside, and locked nucleic acid.
 167. A pharmaceutically acceptablecomposition comprising an antisense oligonucleotide according to claim156, and a pharmaceutically acceptable diluent or carrier.
 168. A methodof treating cancer in a patient in need thereof, comprising:administering to the patient a therapeutically effective amount of thepharmaceutical composition of claim 167, wherein the antisenseoligonucleotide binds to a segment of a pre-mRNA which is encoded byNEDD4L and modulates splicing in the pre-mRNA.
 169. The method of claim168, wherein the cancer comprises lung cancer, kidney cancer, or breastcancer.
 170. The method of claim 168, wherein the breast cancer istriple-negative breast cancer.
 171. A method of modulating splicing of aNEDD4L pre-mRNA in a cell comprising: contacting the cell with anantisense compound selected from the group consisting of: (SEQ ID NO: 1)5′-GTGGGTTTCAGGGATTCTGA-3′, (SEQ ID NO: 2) 5′-CCCTGATTCAGACAGCAGGG-3′,(SEQ ID NO: 3) 5′-GCTGGCTTTGTCTGGATAGG-3′, (SEQ ID NO: 4)5′-TCTCACGTCACCTGCCTTAC-3′, and (SEQ ID NO: 5)5′-AGCGCTGCCACAGCAGTGGG-3′,

or a complement thereof; thereby modulating splicing in the NEDD4Lpre-mRNA of the cell.
 172. The method of claim 171, wherein themodulation of splicing comprises promoting a splicing switch in saidpre-mRNA.
 173. The method of claim 171, wherein the modulation ofsplicing comprises promoting inclusion of an exon in a pre-mRNA isoform.174. A method of treating a patient having a cancer showingdisease-specific splicing events of the pre-mRNA encoded by the NEDD4Lgene resulting in a short pre-mRNA isoform, comprising: contacting thecell of the patient with an ASO, wherein the ASO binds to a segment ofthe pre-mRNA and modulates splicing of the pre-mRNA from the shortisoform to a long isoform, thereby treating the cancer.
 175. The methodof claim 174, wherein the ASO promotes inclusion of an excluded middleexon of an identified exon trio in the pre-mRNA.